Template-fixed peptidomimetics as medicaments against HIV and cancer

ABSTRACT

Template-fixed β-hairpin peptidomimetics of the General Formula (I); wherein Z 1  and Z 2  are template-fixed chains of 4 and 6 or 5 and 7 α-amino acid residues and salts thereof. They have CXCR4-antagonizing properties and can be used as medicaments. These β-sheet peptidomimetics can be manufactured by a process which is based on a mixed solid- and solution phase synthetic strategy.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a National Stage filing in the U.S. of InternationalApplication No. PCT/EP2003/004641, filed May 2, 2003, the contents ofwhich are incorporated by reference herein.

The present invention provides template-fixed β-hairpin peptidomimeticsincorporating two template-fixed chains of 4 and 6 or 5 and 7 α-aminoacid residues which, depending on their positions in the chains, are Glyor Pro, or of certain types, as defined herein below. Thesetemplate-fixed β-hairpin mimetics have antagonizing CXCR4-activity. Inaddition, the present invention provides an efficient synthetic processby which these compounds can, if desired, be made in parallellibrary-format. These O-hairpin peptidomimetics show improved efficacy,bioavailability, half-life and most importantly a significantly enhancedratio between antagonizing CXCR4 activity on the one hand, and hemolysison red blood cells and cytotoxicity on the other.

To date the available therapies for the treatment of HIV infections havebeen leading to a remarkable improvement in symptoms and recovery fromdisease in infected people. Although the highly active anti retroviraltherapy (HAART-therapy) which involves a combination of reversetranscriptase/protease inhibitor has dramatically improved the clinicaltreatment of individuals with AIDS or HIV infection, there have stillremained several serious problems including multi drug resistance,significant adverse effects and high costs. Particularly desired areanti HIV agents that block the HIV infection at an early stage of theinfection, such as the viral entry.

It has recently been recognized that for efficient entry into targetcell, human immunodeficiency viruses require the chemokine receptorsCCR5 and CXCR4 as well as the primary receptor CD4 (N. Levy, Engl. J.Med., 335, 29, 1528-1530). Accordingly, an agent which could block theCXCR4 chemokine receptors should prevent infections in healthyindividuals and slow or halt viral progression in infected patients(Science, 1997, 275, 1261-1264).

Among the different types of CXCR4 inhibitors (M. Schwarz, T. N. C.Wells, A. E. I. Proudfoot, Receptors and Channels, 2001, 7,417428), oneemerging class is based on naturally occurring cationic peptideanalogues derived from Polyphemusin II which have an antiparallelβ-sheet structure, and a β-hairpin that is maintained by two disulfidebridges (H. Nakashima, M. Masuda, T. Murakamni, Y. Koyanagi, A.Matsumoto, N. Fujii, N. Yamamoto, Antimicrobial Agents and Chemoth.1992, 36, 1249-1255; H. Tamamura, M. Kuroda, M. Masuda, A. Otaka, S.Funakoshi, H. Nakashima, N. Yamamoto, M. Waki, A. Matsumotu, J. M.Lancelin, D. Kohda, S. Tate, F. Inagaki, N. Fujii, Biochim. Biophys.Acta 1993, 209, 1163; WO 95/10534 A1).

Synthesis of structural analogs and structural studies by nuclearmagnetic resonance (NMR) spectroscopy have shown that the cationicpeptides adopt well defined β-hairpins conformations, due to theconstraining effect of the single or two disulfide bridges (H. Tamamura,M. Sugioka, Y. Odagaki, A. Omagari, Y. Kahn, S. Oishi, H. Nakashima, N.Yamamoto, S. C. Peiper, N. Hamanaka, A. Otaka, N. Fujii, Bioorg. Med.Chem. Lett. 2001, 359-362). These results show that the β-hairpinstructure plays an important role in antagonizing CXCR4-activity.

Additional structural studies have also indicated that the antagonizingactivity can also be influenced by modulating amphiphilic structure andthe pharmacophore (H. Tamamura, A. Omagari, K. Hiramatsu, K. Gotoh, T.Kanamoto, Y. Xu, E. Kodama, M. Matsuoka, T. Hattori, N. Yamamoto, H.Nakashima, A. Otaka, N. Fujii, Bioorg. Med. Chem. Lett. 2001, 11,1897-1902; H. Tamamura, A. Omagari, K. Hiramatsu, S. Oishi, H.Habashita, T. Kanamoto, K. Gotoh, N. Yamamoto, H. Nakashima, A. Otaka N.Fujii, Bioorg. Med. Chem. 2002, 10, 1417-1426; H. Tamamura, K.Hiramatsu, K. Miyamoto, A. Omagari, S. Oishi, H. Nakashima, N. Yamamoto,Y. Kuroda, T. Nakagawa, A. Otaki, N. Fujii, Bioorg. Med. Chem. Letters2002, 12, 923-928).

A key issue in the design of CXCR4 antagonizing peptides is selectivity.The Polyphemusin II derived analogs exert still a cytotoxicity despiteimprovements (K. Matsuzaki, M. Fukui, N. Fujii, K. Miyajima, Biochim.Biophys. Acta 1991, 259, 1070; A. Otaka, H. Tamamura, Y. Terakawa, M.Masuda, T. Koide, T. Murakami, H. Nakashima, K. Matsuzaki, K. Miyajima,T. Ibuka, M. Waki, A. Matsumoto, N. Yamamoto, N. Fujii Biol. Pharm.Bull. 1994, 17, 1669 and references cited above.

This cytotoxic activity essentially obviates use in vivo, and representsa serious disadvantage in clinical applications. Before intravenous usecan be considered, the general toxicity, protein-binding activity inblood serum, as well as protease stability become serious issues whichmust be adequately addressed.

In addition it has recently been discovered, that the CXCR4-receptor isinvolved in chemotactic activity of cancer cells, such as breast cancermetastasis or ovarian cancer (A. Muller, B. Homey, H. Soto, N. Ge, D.Catron, M. E. Buchanan, T. Mc Clanahan, E. Murphey, W. Yuan, S. N.Wagner, J. Luis Barrera, A. Mohar, E. Verastegui, A. Ziotnik, Nature2001, 50, 410, J. M. Hall, K. S. Korach, Molecular Endocrinology, 2003,1-47;), Non-Hodgin's Lymphoma (F. Bertolini, C. DellAgnola, P. Manusco,C. Rabascio, A. Burlini, S. Monestiroli, A. Gobbi, G. Pruneri, G.Martinelli, Cancer Research 2002, 62, 3106-3112), or lung cancer (T.Kijima, G. Maulik, P. C. Ma, E. V. Tibaldi, R: E. Turner, B. Rollins, M.Sattler, B. E. Johnson, R. Salgia, Cancer Research 2002, 62, 6304-6311)or in inflammatory diseases e.g. such as rheumatoid arthritis, asthma,or multiple sclerose (K. R Shadidi et al, Scandinavian Journal ofImmunolgy, 2003, 57, 192-198, J. A. Gonzalo J. Immunol. 2000, 165,499-508, S. Hatse et al, FEBS Letters 2002 527, 255-262 and citedreferences). Blocking the chemotactic activity with a CXCR4 inhibitorshould stop the migration of cancer cells. The mediation of recruitmentof immunecells to sites of inflammation should be stopped by a CXCR4inhibitor. Particularly desired are agents for treatment of cancer oragents for treatment of inflammatory disorders.

In the compounds described below, a new strategy is introduced tostabilize beta-hairpin conformations in bridged-backbone peptide mimeticexhibiting high CXCR4 antagonizing activity and anticancer activity andanti inflammatory activity. This involves transplanting the cationic andhydrophobic hairpin sequence onto a template, whose function is torestrain the peptide loop backbone into a hairpin geometry. The rigidityof the hairpin may be further influenced by introducing a disulfidebridge. Template-bound hairpin mimetic peptides have been described inthe literature (D, Obrecht, M. Altorfer, J. A. Robinson, Adv. Med. Chem.1999, 4, 1-68; J. A. Robinson, Syn. Lett. 2000, 4, 429-441), but suchmolecules have not previously been evaluated for development of CXCR4antagonizing peptides. However, the ability to generate β-hairpinpeptidomimetics using combinatorial and parallel synthesis methods hasnow been established (L. Jiang, K. Moehle, B. Dhanapal, D. Obrecht, J.A. Robinson, Helv. Chim. Acta. 2000, 83, 3097-3112).

These methods allow the synthesis and screening of large hairpin mimeticlibraries, which in turn considerably facilitates structure-activitystudies, and hence the discovery of new molecules with highly potentCXCR4 antagonizing activity or anti cancer activity or anti inflammatoryactivity and low hemolytic activity to human red blood blood cells.β-Hairpin peptidomimetics obtained by the approach described here areuseful as Anti-HIV agents and anticancer agents and anti-inflammatoryagents.

The β-hairpin peptidomimetics of the present invention are compounds ofthe general formula

is a group of one of the formulae

is the residue of an L-α-amino acid with B being a residue of formula—NR²⁰CH(R⁷¹)—; or the enantiomer of one of the groups A1 to A69 asdefined hereinafter; or, in case the template is of type (a4), also aresidue of an amino acid with B being a residue of formula—NR²⁰—CH₂—C₆H₄—CH₂—;

is a group of one of the formulae

-   R¹ is H; lower alkyl; or aryl-lower alkyl;-   R² is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R³ is H; alkyl; alkenyl; —CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁵ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁶ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶¹) ₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄ ⁸;-   R⁷ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷;    —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s) C₆H₄R⁸;-   R⁸ is H; Cl; F; CF₃; NO₂; lower alkyl; lower alkenyl; aryl;    aryl-lower alkyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)COR⁶⁴;-   R⁹ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; (CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹⁰ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹¹ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;    —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s) C₆H₄R⁸;-   R¹² is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(r)(CHR⁶¹)_(s)COOR⁵⁷; (CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(r)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹³ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(q)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(q)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(q)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(q)(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷;    —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(q)(CHR⁶¹)_(s)SOR⁶²; or —(CH₂)_(q)(CHR⁶¹)_(s) C₆H₄R⁸;-   R¹⁵ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R^(β); or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹⁶ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹), SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹⁷ is alkyl; alkenyl; —(CH₂)_(q)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(q)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(q)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(q)(CHR⁶¹)_(s)OCONW³³R⁷⁵; —(CH₂)_(q)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(q)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(q)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(q)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(q)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(q)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹⁸ is alkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(p)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R¹⁹ is lower alkyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(p)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶)₂; —(CH₂)_(p)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶)_(s)C₆H₄R⁸; or-   R¹⁸ and R¹⁹ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;    —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;-   R²⁰ is H; alkyl; alkenyl; or aryl-lower alkyl;-   R²¹ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R²² is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R²³ is alkyl; alkenyl; —CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)₈C₆H₄R⁸;-   R²⁴ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R²⁵ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;    —CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(r)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R²⁶ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(m)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸; or-   R²⁵ and R²⁶ taken together can form: —CH₂)₂₋₆—;    —(CH₂)_(r)O(CH₂)_(r)—; —(CH₂)_(r)S(CH₂)_(r)—; or    —(CH₂)_(r)NR⁵⁷(CH₂)_(r)—;-   R²⁷ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R²⁸ is alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)—OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s) SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s) NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCON³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NRCONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s) COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s) CONR⁵⁸R⁵⁹;    —CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s) C₆H₄R⁸;-   R²⁹ is alkyl; alkenyl; —CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R³⁰ is H; alkyl; alkenyl; or aryl-lower alkyl;-   R³¹ is H; alkyl; alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;    —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R³² is H; lower alkyl; or aryl-lower alkyl;-   R³³ is H; alkyl, alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²;    —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COR⁶⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)—CONR⁵⁸R⁵⁹, —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(o)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄T⁸;-   R³⁴ is H; lower alkyl; aryl, or aryl-lower alkyl;-   R³³ and R³⁴ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;    —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;-   R³⁵ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;    —(CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s) C₆H₄R⁸;-   R³⁶ is H, alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)COOR⁵⁷;    (CH₂)_(p)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(p)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶′)_(s) C₆H₄R⁸;-   R³⁷ is H; F; Br; Cl; NO₂; CF₃; lower alkyl;    —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R³⁸ is H; F; Br; Cl; NO₂; CF₃; alkyl; alkenyl;    —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s)C₆H₄R⁸;-   R³⁹ is H; alkyl; alkenyl; or aryl-lower alkyl;-   R⁴⁰ is H; alkyl; alkenyl; or aryl-lower alkyl;-   R⁴¹ is H; F; Br; Cl; NO₂; CF₃; alkyl; alkenyl;    —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(p)(CHR⁶¹)_(s)OCONT³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)—(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s) C₆H₄R⁸;-   R⁴² is H; F; Br; Cl; NO₂; CF₃; alkyl; alkenyl;    —(CH₂)_(p)(CHR⁶¹)_(s)OR⁵⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(o)(CHR⁶¹)_(s) C₆H₄R⁸;-   R⁴³ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁵⁷;    (CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷;    —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CHR⁶¹)_(s)PO(OR⁶⁰)₂;    —(CH₂)_(o)(CHR⁶¹)_(s)SO₂R⁶²; or —(CH₂)_(o)(CHR⁶¹)_(s) C₆H₄R⁸;-   R⁴⁴ is alkyl; alkenyl; —(CH₂)_(r)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(r)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(r)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(r)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(r)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)₂(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(r)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(r)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(r)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(r)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁴⁵ is H; alkyl; alkenyl; —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(o)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(o)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(o)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(s)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(s)(CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CH₂)_(r)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(s)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁴⁶ is H; alkyl; alkenyl; or —(CH₂)_(o)(CHR⁶¹)_(p)C₆H₄R⁸;-   R⁴⁷ is H; alkyl; alkenyl; or —(CH₂)_(o)(CHR⁶¹)_(s)OR⁵⁵;-   R⁴⁸ is H; lower alkyl; lower alkenyl; or aryl-lower alkyl;-   R⁴⁹ is H; alkyl; alkenyl; —(CHR⁶¹)_(s)COOR⁵⁷; (CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    (CHR⁶¹)_(s)PO(OR⁶⁰)₂; —(CHR⁶¹)_(s)SOR⁶²; or —(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁵⁰ is H; lower alkyl; or aryl-lower alkyl;-   R⁵¹ is H; alkyl; alkenyl; —(CH₂)_(m)(CH⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s)SO₂R⁶²; or    —(CH₂)_(p)(CHR⁶¹)_(s)C₆H⁸;-   R⁵² is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NRR³³R³⁴;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁵⁷; —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;    —(CH₂)_(o)(CHR⁶¹)_(p)PO(OR⁶⁰)₂; —(CH₂)_(p)(CHR⁶¹)_(s) SO₂R⁶²; or    —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁵³ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)SR⁵⁶; —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁵⁷R;    —(CH₂)_(m)(CHR⁶¹)_(s)NR²OCONR³³R⁸²; —(CH₂)_(m)(CHR⁶¹)_(s)COOR⁵⁷;    —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; —(CH₂)_(o)(CR⁶¹)_(p)PO(OR⁶⁰)₂;    —(CH₂)_(p)(CHR⁶¹)_(s) SO₂R⁶²; or —(CH₂)_(p)(CHR⁶¹)_(s)C₆H₄R⁸;-   R⁵⁴ is H; alkyl; alkenyl; —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR³³R³⁴; —(CH₂)_(m)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR³³R⁸²; —(CH₂)_(o)(CHR⁶¹)COOR⁵⁷;    —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹; or —(CH₂)_(o)(CHR⁶¹)_(s) C₆H₄R⁸;-   R⁵⁵ is H; lower alkyl; lower alkenyl; aryl-lower alkyl;    —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁷; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³;    —(CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)—COR⁶⁴; —(CH₂)_(o)(CHR⁶¹)COOR⁵⁷; or    —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;-   R⁵⁶ is H; lower alkyl; lower alkenyl; aryl-lower alkyl;    —(CH₂)_(m)(CHR⁶¹)_(s)OR⁵⁷; —(CH₂)_(m)(CHR⁶¹)_(s)NR³⁴R⁶³;    (CH₂)_(m)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²; —(CH₂)_(m)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²;    —(CH₂)_(o)(CHR⁶¹)_(s)—COR⁶⁴; or —(CH₂)_(o)(CHR⁶¹)_(s)CONR⁵⁸R⁵⁹;-   R⁵⁷ is H; lower alkyl; lower alkenyl; aryl lower alkyl; or    heteroaryl lower alkyl;-   R⁵⁸ is H; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower    alkyl; or heteroaryl-lower alkyl;-   R⁵⁹ is H; lower alkyl; lower alkenyl; aryl; heteroaryl; aryl-lower    alkyl; or heteroaryl-lower alkyl; or-   R⁵⁸ and R⁵⁹ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;    —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;-   R⁶⁰ is H; lower alkyl; lower alkenyl; aryl; or aryl-lower alkyl;-   R⁶¹ is alkyl; alkenyl; aryl; heteroaryl; aryl-lower alkyl;    heteroaryl-lower alkyl; —(CH₂)_(m)OR⁵⁵; —(CH₂)_(m)NR³³R³⁴;    —(CH₂)_(m)OCONR⁷⁵R⁸²; —(CH₂)_(m)NR²⁰CONR⁷⁸R⁸²; —(CH₂)_(o)COOR³⁷;    —(CH₂)_(o)NR⁵⁸R⁵⁹; or —(CH₂)_(o)PO(COR⁶⁰)₂;-   R⁶² is lower alkyl; lower alkenyl; aryl, heteroaryl; or aryl-lower    alkyl;-   R⁶³ is H; lower alkyl; lower alkenyl; aryl, heteroaryl; aryl-lower    alkyl; heteroaryl-lower alkyl; —COR⁶⁴; —COOR⁵⁷; —CONR⁵⁸R⁵⁹; —SO₂R⁶²;    or —PO(OR⁶⁰)₂;-   R³⁴ and R⁶³ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;    —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;-   R⁶⁴ is H; lower alkyl; lower alkeriyl; aryl; heteroaryl; aryl-lower    alkyl; heteroaryl-lower alkyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁶⁵;    —(CH₂)_(p)(CHR⁶¹)_(s)SR⁶⁶; or —(CH₂)_(p)(CHR⁶¹)_(s)NR³⁴R⁶³;    —(CH₂)_(p)(CHR⁶¹)_(s)OCONR⁷⁵R⁸²; —(CH₂)_(p)(CHR⁶¹)_(s)NR²⁰CONR⁷⁸R⁸²;-   R⁶⁵ is H; lower alkyl; lower alkenyl; aryl, aryl-lower alkyl;    heteroaryl-lower alkyl; —COR⁵⁷; —COOR⁵⁷; or —CONR⁵⁸R⁵⁹;-   R66 is H; lower alkyl; lower alkenyl; aryl; aryl-lower alkyl;    heteroaryl-lower alkyl; or —CONR⁵⁸R⁵⁹;

Z and Z¹ are chains of n and, respectively, n′ α-amino acid residueswhereby either n is 4 and n′ is 6 or n is 5 and n′ is 7, the positionsof said amino acid residues in said chain Z being counted starting fromthe N-terminal amino acid and the positions of said amino acid residuesin said chain Z¹ being counted starting from the C-terminal amino acid,whereby these amino acid residues are, depending on their position inthe chains, Gly, or Pro, or of one of the types

-   C: —NR²⁰CH(R⁷²)CO—;-   D: —NR²⁰CH(F⁷³)CO—;-   E: —NR²⁰CH(R⁷⁴)CO—;-   F: —NR²⁰CH(R⁸⁴)CO—; and-   H: —NR²⁰—CH(CO—)—(CH₂)₄₋₇—CH(CO—)—NR²⁰—;    —NR²⁰—CH(CO—)—(CH₂)_(p)SS(CH₂)_(p)—CH(CO—)—NR²⁰—;    —NR²⁰—CH(CO—)—(—(CH₂)_(p)NR²⁰CO(CH₂)_(p)—CH(CO—)—NR²⁰—;    —NR²⁰—CH(CO—)—(—(CH₂)_(p)NR²⁰CONR²⁰(CH₂)_(p)—CH(CO—)—NR²⁰—; and-   I: —NR⁸⁶CH₂CO—;-   R⁷¹ is lower alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁷⁵;    —(CH₂)_(p)(CHR⁶¹)_(p)SR⁷⁵; —(CH₂)_(p)(CHR⁶¹)_(s)OCONR³³R⁷⁵;    —(CH₂)_(o)(CHR⁶¹)_(s)COOR⁷⁵; —(CH₂)_(p)CONR⁵⁸R⁵⁹;    —(CH₂)_(p)PO(OR⁶²)₂; —(CH₂)_(p)SO₂R⁶²; or    —(CH₂)_(o)—C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶;-   R⁷² is H, lower alkyl; lower alkenyl; —(CH₂)_(p)(CHR⁶¹)_(s)OR⁸⁵; or    —(CH₂)_(p)(CHR⁶¹)_(s)SR⁸⁵;-   R⁷³ is —(CH₂)_(o)R⁷⁷; —(CH₂)_(r)O(CH₂)_(o)R⁷⁷;    —(CH₂)_(r)S(CH₂)_(o)R⁷⁷; or —(CH₂)_(r)NR²⁰(CH₂)_(o)R⁷⁷;-   R⁷⁴ is —(CH₂)_(p)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁷⁷R⁸⁰;    —(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(p)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰; —(CH₂)_(p)C₆H₄NR⁷⁸R⁷⁹;    —(CH₂)_(p)C₆H₄NR⁷⁷R⁸⁰; —(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)C₆C₄C(—NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;    —(CH₂)_(p)C₆H₄NR⁸⁰(═NOR⁵⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(p)C₆H₄N═C(NR⁷⁸R⁷⁹)NR⁷⁹R⁸⁰; —(CH₂)_(r)O(CH₂)_(m)NR⁷⁸R⁷⁹;    —(CH₂)_(r)O(CH₂)_(m)NR⁷⁷R⁸⁰; —(CH₂)_(r)O(CH₂)_(p)C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(r)O(CH₂)_(p)C(—NOR⁵⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(r)O(CH₂)_(p)C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;    —(CH₂)_(r)O(CH₂)_(m)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(r)O(CH₂)_(m)N═C(NR⁷⁸R⁸⁰)NR⁷⁹R⁸⁰;    —(CH₂)_(r)O(CH₂)_(p)C₆H₄CNR⁷⁸R⁷⁹;    —(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(r)O(CH₂)_(p)C₆H₄C(—NOR⁵⁰NR⁷⁸R⁷⁹;    —(CH₂)_(r)O(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;    —(CH₂)_(r)S(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(r)S(CH₂)_(m)NR⁷⁸R⁷⁹; —(CH₂)_(r)S(CH₂)_(m)NR⁷⁷R⁸⁰;    —(CH₂)_(r)S(CH₂)_(p)C(═NR⁸⁰)_(m)NR⁷⁸R⁷⁹;    —(CH₂)_(r)S(CH₂)_(p)C(═NOR⁵⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(r)S(CH₂)_(p)C(═NNR⁷⁹R⁷⁹)⁸R⁷⁹;    —(CH₂)_(r)S(CH₂)_(m)NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(r)S(CH₂)_(m)N═C(R⁷⁸R⁸⁰)NR⁷⁹R⁸⁰—(CH₂)_(r)S(CH₂)_(p)C₆C₄CNR⁷⁸R⁷⁹;    —(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NR⁸⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NOR⁵⁰)NR⁷⁸R⁷⁹;    —(CH₂)_(r)S(CH₂)_(p)C₆H₄C(═NNR⁷⁸R⁷⁹)NR⁷⁸R⁷⁹;    —(CH₂)_(r)S(CH₂)_(p)C₆H₄NR⁸⁰C(═NR⁸⁰)NR⁷⁸R⁷⁹; —(CH₂)_(p)NR⁸⁰COR⁶⁴;    —(CH₂)_(p)NR⁸⁰COR⁷⁷; —(CH₂)_(p)NR⁸⁰CONR⁷⁸R⁷⁹; or    —(CH₂)_(p)C₆H₄NR⁸⁰CON⁷⁸R⁷⁹;-   R⁷⁵ is lower alkyl; lower alkenyl; or aryl-lower alkyl;-   R³³ and R⁷⁵ taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;    —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;-   R⁷⁵ and R⁸² taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;    —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;-   R⁷⁶ is H; lower alkyl; lower alkenyl; aryl-lower alkyl;    —(CH₂)_(o)OR⁷²; —(CH₂)₂SR⁷²; —(CH₂)_(o)NR³³R³⁴;    —(CH₂)_(o)OCONR³³R⁷⁵; —(CH₂)_(o)NR²⁰CONR³³R⁸²; —(CH₂)_(o)COOR⁷⁵;    —(CH₂)_(o)CONR⁵⁸R⁵⁹; —(CH₂)_(o)PO(OR⁶⁰)₂; —(CH₂)_(p)SO₂R⁶²; or    —(CH₂)_(o)COR⁶⁴;-   R⁷⁷ is —C₆R⁶⁷R⁶⁸R⁶⁹R⁷⁰R⁷⁶; or a heteroaryl group of one of the    formulae

-   R⁷⁸ is H; lower alkyl; aryl; or aryl-lower alkyl;-   R⁷⁸ and R⁸² taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;    —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;-   R⁷⁹ is H; lower alkyl; aryl; or aryl-lower alkyl; or-   R⁷⁸ and R⁷⁹, taken together, can be —(CH₂)₂₋₇—; —(CH₂)₂O(CH₂)₂—; or    —(CH₂)₂NR⁵⁷(CH₂)₂—;-   R⁸⁰ is H; or lower alkyl;-   R⁸¹ is H; lower alkyl; or aryl-lower alkyl;-   R⁸² is H; lower alkyl; aryl; heteroaryl; or aryl-lower alkyl;-   R³³ and R⁸² taken together can form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;    —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—;-   R⁸³ is H; lower alkyl; aryl; or —NR⁷⁸R⁷⁹;-   R⁸⁴ is —(CH₂)_(p)CONR⁷⁷R⁷⁹; —(CH₂)_(p)NR⁸⁰CONR⁷BR⁷⁹;    —(CH₂)_(p)C₆H₄CONR⁷⁸R⁷⁹; or —(CH₂)_(p)C₆H₄NR⁸⁰CONR⁷⁸R⁷⁹;-   R⁸⁵ is lower alkyl; or lower alkenyl;-   R⁸⁶ is R⁷⁴; —[(CH₂)_(u)—X]_(t)—CH₂)_(v)NR⁷⁸R⁷⁹;    —[(CH₂)_(u)—X]_(t)—(CH₂)_(v)—C(═NR⁸⁰)NR⁷⁸R⁷⁹; X is —O—, —NR²⁰—, —S—,    OCOO—, u is 1-3, t is 1-6, v is 1-3;    with the proviso that in said chains Z and Z¹ of n and,    respectively, n′ α-amino acid residues    -   if n is 4 and n′ is 6, the amino acid residues in positions 1 to        4 of Z and in positions 1′ to 6′ of Z¹ are:        -   P1: of type C or of type D or of type E or of type F, or the            residue is Pro;        -   P2: of type E or of type F;        -   P3: of type F, or the residue is Pro;        -   P4: of type E;        -   P1′: of type C or of type D or of type E or of type F, or            the residue is Gly;        -   P2′: of type D or of type C;        -   P3′: of type F or the residue is Pro;        -   P4′: of type D or of type C;        -   P5′: of type E, or of type F or the residue is Pro; and        -   P6′: of type E or of type F, or the residue is Pro; or        -   P3 and P3′, taken together, can form a group of type H;            and    -   if n is 5 and n′ is 7, the amino acid residues in positions 1 to        5 of Z and in positions 1′ to 7′ of Z¹ are:        -   P1: of type C or of type D or of type E or of type F, or the            residue is Pro;        -   P2: of type E or of type F;        -   P3: of type F, or the residue is Pro;        -   P4: of type F;        -   P5: of type E        -   P1′: of type C or of type D or of type E or of type F, or            the residue is Pro;        -   P2′: of type F;        -   P3′: of type D or the residue is Pro;        -   P4′: of type E or of type F;        -   P5′: of type D, or the residue is Pro;        -   P6′: of type E or of type F, or the residue is Pro; and        -   P7′: of type E or of type I, or the residue is Gly; or        -   P2 and P2′ and/or P4 and P4′, taken together, can form a            group of type H; at P7′ also D-isomers being possible,            and pharmaceutically acceptable salts thereof.

In accordance with the present invention these β-hairpin peptidomimeticscan be prepared by a process which comprises

-   (a) coupling an appropriately functionalized solid support with an    appropriately N-protected derivative of that amino acid which in the    desired end-product is in position 4 of Z if n is 4 or in position 5    of Z if n is 5, any functional group which may be present in said    N-protected amino acid derivative being likewise appropriately    protected;-   (b) removing the N-protecting group from the product thus obtained;-   (c) coupling the product thus obtained with an appropriately    N-protected derivative of that amino acid which in Z of the desired    end-product is one position nearer the N-terminal amino acid    residue, any functional group which may be present in said    N-protected amino acid derivative being likewise appropriately    protected;-   (d) removing the N-protecting group from the product thus obtained;-   (e) repeating steps (c) and (d) until the N-terminal amino acid    residue of Z has been introduced;-   (f) coupling the product thus obtained with a compound of the    general formula

-    is as defined above and X is an N-protecting group or, if

-    is to be group (a1), or (a2), above, alternatively    -   (fa) coupling the product obtained in step (e) with an        appropriately N-protected derivative of an amino acid of the        general formula        HOOC—B—H III or HOOC-A-H IV    -    wherein B and A are as defined above, any functional group        which may be present in said N-protected amino acid derivative        being likewise appropriately protected;    -   (fb) removing the N-protecting group from the product thus        obtained; and    -   (fc) coupling the product thus obtained with an appropriately        N-protected derivative of an amino acid of the above general        formula IV and, respectively, m, any functional group which may        be present in said N-protected amino acid derivative being        likewise appropriately protected; or        if

is to be group (a3), above, alternatively

-   -   (fa′) coupling the product obtained in step (e) with an        appropriately N-protected derivative of an amino acid of the        above general formula III, any functional group which may be        present in said N-protected amino acid derivative being likewise        appropriately protected;    -   (fb′) removing the N-protecting group from the product thus        obtained; and    -   (fc′) coupling the product thus obtained with an appropriately        N-protected derivative of an amino acid of the above general        formula m, any functional group which may be present in said        N-protected amino acid derivative being likewise appropriately        protected;

-   (g) removing the N-protecting group from the product obtained in    step (f) or (fc) or (fc);

-   (h) coupling the product thus obtained with an appropriately    N-protected derivative of that amino acid which in the desired    end-product is in position 1 of Z¹, any functional group which may    be present in said N-protected amino acid derivative being likewise    appropriately protected;

-   (i) removing the N-protecting group from the product thus obtained;

-   (j) coupling the product thus obtained with an appropriately    N-protected derivative of that amino acid which in the desired    end-product is one position farther away from position 1 of Z¹, any    functional group which may be present in said N-protected amino acid    derivative being likewise appropriately protected;

-   (k) removing the N-protecting group from the product thus obtained;

-   (l) repeating steps (j) and (k) until all amino acid residues of Z¹    have been introduced;

-   (m) if desired, selectively deprotecting one or several protected    functional group(s) present in the molecule and appropriately    substituting the reactive group(s) thus liberated;

-   (n) if desired, forming one or two interstrand linkage(s) between    side-chains of appropriate amino acid residues at opposite positions    of the O-strand region;

-   (o) detaching the product thus obtained from the solid support and    removing any protecting groups present on functional groups of any    members of the chain of amino acid residues and, if desired, any    protecting group(s) which may in addition be present in the    molecule; and

-   (p) if desired, converting the product thus obtained into a    pharmaceutically acceptable salt or converting a pharmaceutically    acceptable, or unacceptable, salt thus obtained into the    corresponding free compound of formula I or into a different,    pharmaceutically acceptable, salt.

Introducing an amino acid residue of type I can, alternatively, beeffected by coupling with a leaving group-containing acetylating agent,such as bromo, chloro or iodo acetic acid, followed by nucleophilicdisplacement with an amine of the formula H₂NR⁸⁶ which, if necessary, isappropriately protected.

The peptidomimetics of the present invention can also be enantiomers ofthe compounds of formula I. These enantiomers can be prepared by amodification of the above process in which enantiomers of all chiralstarting materials are used.

As used in this description, the term “alkyl”, taken alone or incombinations, designates saturated, straight-chain or branchedhydrocarbon radicals having up to 24, preferably up to 12, carbon atoms.Similarly, the term “alkenyl” designates straight chain or branchedhydrocarbon radicals having up to 24, preferably up to 12, carbon atomsand containing at least one or, depending on the chain length, up tofour olefinic double bonds. The term “lower” designates radicals andcompounds having up to 6 carbon atoms. Thus, for example, the term“lower alkyl” designates saturated, straight-chain or branchedhydrocarbon radicals having up to 6 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, sec.-butyl, isobutyl, tert.-butyl and thelike. The term “aryl” designates aromatic carbocyclic hydrocarbonradicals containing one or two six-membered rings, such as phenyl ornaphthyl, which may be substituted by up to three substituents such asBr, Cl, F, CF₃, NO₂, lower alkyl or lower alkenyl. The term “heteroaryl”designates aromatic heterocyclic radicals containing one or two five-and/or six-membered rings, at least one of them containing up to threeheteroatoms selected from the group consisting of O, S and N and saidring(s) being optionally substituted; representative examples of suchoptionally substituted heteroaryl radicals are indicated hereinabove inconnection with the definition of R⁷⁷.

The structural element -A-CO— designates amino acid building blockswhich in combination with the structural element —B—CO— form templates(a1) and (a2). The structural element —B—CO— forms either alone or incombination with another structural element —B—CO— templates (a4) and(a3). Templates (a) through (p) constitute building blocks which have anN-terminus and a C-terminus oriented in space in such a way that thedistance between those two groups may lie between 4.0-5.5A. A peptidechain Z is linked to the C-terminus of the templates (a) through (p) viathe N-terminus, and the corresponding N-terminus of the template islinked to the C-terminus of Z¹ to form a β-hairpin structure such asthat depicted in formula I. In a case as here where the distance betweenthe N— and C— termini of the template lies between 4.0-5.5A the templatewill induce the H-bond network necessary for the formation of aβ-hairpin conformation within the peptide chain Z and Z¹. Thus templateand peptide chains form a β-hairpin mimetic. The β-hairpin conformationis highly relevant for the CXCR4 antagonizing activity of the β-hairpinmimetics of the present invention.

Building blocks A1-A69 belong to a class of amino acids wherein theN-terminus is a secondary amine forming part of a ring. Among thegenetically encoded amino acids only proline falls into this class. Theconfiguration of building block A1 through A69 is (D), and they arecombined with a building block —B—CO— of (L)-configuration. Preferredcombinations for templates (a1) are-^(D)A1-CO—^(L)B—CO— to^(D)A69-CO—^(L)B—CO—. Thus, for example, ^(D)Pro-^(L)Pro constitutes theprototype of templates (a1). Less preferred, but also possible arecombinations where templates (a2) are -^(L)A1-CO—^(D)B—CO— to^(L)A69-CO—^(D)B—CO—. Thus, for example, ^(L)Pro-^(D)Pro constitutes aless preferred prototype of template (a2).

It will be appreciated that building blocks -A1-CO— to -A69-CO— in whichA has (D)-configuration, are carrying a group R¹ at the α-position tothe N-terminus. The preferred values for R¹ are H and lower alkyl withthe most preferred values for R¹ being H and methyl. It will berecognized by those skilled in the art, that A1-A69 are shown in(D)-configuration which, for R¹ being H and methyl, corresponds to the(R)-configuration. Depending on the priority of other values for R¹according to the Cahn, Ingold and Prelog-rules, this configuration mayalso have to be expressed as (S).

In addition to R¹ building blocks -A1-CO— to -A69-CO— can carry anadditional substituent designated as R² to R¹⁷. This additionalsubstituent can be H, and if it is other than H, it is preferably asmall to medium-sized aliphatic or aromatic group. Examples of preferredvalues for R² to R¹⁷ are:

-   -   R²: H; lower alkyl; lower alkenyl; (CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); (CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); (CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; R⁵⁷: H; or lower alkyl);        (CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or lower        alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl;        R⁶⁴; lower alkyl; or lower alkenyl); —(CH₂)₀COOR⁵⁷ (where R⁵⁷:        lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸:        lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); (CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R⁴: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —CH₂)_(m)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴:        lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷:        lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸:        lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R⁵: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower        alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; R⁵⁷: where H; or lower alkyl);        (CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H; or        lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); (CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴:        alkyl; alkenyl; aryl; and aryl-lower alkyl; heteroaryl-lower        alkyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower        alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower        alkenyl; and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken        together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶j:        lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl;        or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R⁷: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵: lower        alkyl; or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); (CH₂)_(q)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        (CH₂)_(q)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H; or        lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(q)N²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴:        lower alkyl; or lower alkenyl); —(CH₂)_(r)COOR⁵⁷ (where R⁵⁷:        lower alkyl; or lower alkenyl); —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸:        lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); (CH₂)_(r)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵        (where R⁵⁵: lower alkyl; or lower alkenyl); (CH₂)_(o)SR⁵⁶ (where        R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where        R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or        R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H; or        lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl;        or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)_(r); —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower        alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower        alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F;        Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).    -   R⁹: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵: lower        alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷s: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₄—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl;        or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁶² (where R⁶²: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R¹⁰: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl; R⁶⁴:        lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷:        lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸:        lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸        and R⁵⁹ taken together form: —(CH₂)₂₋₄—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R¹¹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)NR²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        allyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R¹²: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR¹⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R¹⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(r)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(r)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl;        or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R¹³: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)_(r);        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)_(r); where R⁵⁷: H; or lower        alkyl); —(CH₂)_(q)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(q)NR²OCONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(q)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        Re: lower alkyl; or lower alkenyl); —(CH₂)_(r)COO⁵⁷ (where R⁵⁷:        lower alkyl; or lower alkenyl); —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where R⁵⁸:        lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(r)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   —R¹⁴: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; lower alkyl; R⁶⁴:        lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷:        lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸:        lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R¹⁵: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₄—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); (CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); particularly favoured are        NR²⁰COlower alkyl (R²⁰═H; or lower alkyl); —(CH₂)_(o)COOR⁵⁷        (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹        (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower        alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower        alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower        alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F;        Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).    -   R¹⁶: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R¹⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl;        or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R¹⁷: lower alkyl; lower alkenyl; —(CH₂)_(q)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(q)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(q)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(q)OCONR³³R⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(q)NR²OCONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₄—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where RW⁷: H; or lower        alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(r)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(q)CONR⁵⁸R⁵⁹ (where        R⁵S: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(r)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(r)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).

Among the building blocks A1 to A69 the following are preferred: A5 withR² being H, A8, A22, A25, A38 with R² being H, A42, A47, and A50. Mostpreferred are building blocks of type A8′:

wherein R²⁰ is H or lower alkyl; and R⁶⁴ is alkyl; alkenyl; aryl;aryl-lower alkyl; or heteroaryl-lower alkyl; especially those whereinR⁶⁴ is n-hexyl (A8′-1); n-heptyl (A8′-2); 4-(phenyl)benzyl (A8′-3);diphenylmethyl (A8′-4); 3-amino-propyl (A8′-5); 5-amino-pentyl (A8′-6);methyl (A8′-7); ethyl (A8′-8); isopropyl (A8′-9); isobutyl (A8′-10);n-propyl (A8′-11); cyclohexyl (A8′-12); cyclohexylmethyl (A8′-13);n-butyl (A8′-14); phenyl (A8′-15); benzyl (A8′-16); (3-indolyl)methyl(A8′-17); 2-(3-indolyl)ethyl (A8′-18); (4-phenyl)phenyl (A8′-19); andn-nonyl (A8′-20).

Building block A70 belongs to the class of open-chain α-substitutedα-amino acids, building blocks A71 and A72 to the corresponding β-aminoacid analogues and building blocks A73-A104 to the cyclic analogues ofA70. Such amino acid derivatives have been shown to constrain smallpeptides in well defined reverse turn or U-shaped conformations (C. M.Venkatachalam, Biopolymers, 1968, 6, 1425-1434; W. Kabsch, C Sander,Biopolymers 1983, 22, 2577). Such building blocks or templates areideally suited for the stabilization of β-hairpin conformations inpeptide loops (D. Obrecht, M. Altorfer, J. A. Robinson, “Novel PeptideMimetic Building Blocks and Strategies for Efficient Lead Finding”, Adv.Med. Chem. 1999, Vol. 4, 1-68; P. Balaram, “Non-standard amino acids inpeptide design and protein engineering”, Curr. Opin. Struct. Biol. 1992,2, 845-851; M. Crisma, G. Valle, C. Toniolo, S. Prasad, R. B. Rao, P.Balaram, “β-turn conformations in crystal structures of model peptidescontaining α,α-disubstituted amino acids”, Biopolymers 1995, 35, 1-9; V.J. Hruby, F. Al-Obeidi, W. Kazmierski, BiochenL J. 1990, 268, 249-262).

It has been shown that both enantiomers of building blocks -A70-CO— toA104-CO— in combination with a building block —B—CO— of L-configurationcan efficiently stabilize and induce β-hairpin conformations (D.Obrecht, M. Altorfer, J. A. Robinson, “Novel Peptide Mimetic BuildingBlocks and Strategies for Efficient Lead Finding”, Adv. Med. Chem. 1999,Vol. 4, 1-68; D. Obrecht, C. Spiegler, P. Schönholzer, K. Müller, H.Heimgartner, F. Stierli, Helv. Chim. Acta 1992, 75, 1666-1696; D.Obrecht, U. Bohdal, J. Daly, C. Lehmann, P. Schönholzer, K. Müller,Tetrahedron 1995, 51, 10883-10900; D. Obrecht, C. Lehmnann, C. Ruffieux,P. Schönholzer, K. Müller, Helv. Chim. Acta 1995, 78, 1567-1587; D.Obrecht, U. Bohdal, C. Broger, D. Bur, C. Lehmann, R. Ruffieux, P.Schönholzer, C. Spiegler, Helv. Chim. Acta 1995, 78, 563-580; D.Obrecht, H. Karajiannis, C. Lehmann, P. Schbnholzer, C. Spiegler, Helv.Chim. Acta 1995, 78, 703-714).

Thus, for the purposes of the present invention templates (a1) can alsoconsist of -A70-CO— to A110CO— where building block A70 to A104 is ofeither (D)- or (L)-configuration, in combination with a building block—B—CO— of (L)-configuration.

Preferred values for R²⁰ in A70 to A104 are H or lower alkyl with methylbeing most preferred.

Preferred values for R¹⁸, R¹⁹ and R²¹-R²⁹ in building blocks A70 to A104are the following:

-   -   R¹⁸: lower alkyl.    -   R¹⁹: lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)SR¹⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)N(W²)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(p)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; or lower alkyl;        or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(p)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(o)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R²¹: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower allyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); (CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or (CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R²²: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R²³: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)OR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H; or        lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); particularly favoured are        NR²⁰COlower alkyl (R²⁰═H; or lower alkyl); —(CH₂)_(o)COOR⁵⁷        (where R⁵¹: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹        (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower        alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower        alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower        alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F;        Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy);    -   R²⁴: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); particularly favoured are        NR²⁰COlower alkyl (R²⁰═H; or lower alkyl); —(CH₂)_(o)COOR⁵⁷        (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹        (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower        alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)—PO(OR⁶⁰)₂ (where R⁶⁰: lower        alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower        alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F;        Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy);    -   R²⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R²⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   Alternatively, R²⁵ and R²⁶ taken together can be —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl).    -   R²⁷: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R²⁸: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R²⁹: lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)N^((R) ²⁰)COR⁶⁴(where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); particularly favored are        NR²⁰COlower-alkyl (R²⁰═H; or lower alkyl); —(CH₂)_(o)COOR⁵⁷        (where R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹        (where R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower        alkyl; or R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower        alkyl; or lower alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower        alkyl; or lower alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F;        Cl; CF₃; lower alkyl; lower alkenyl; or lower alkoxy).

For templates (b) to (p), such as (b1) and (c1), the preferred valuesfor the various symbols are the following:

-   -   R⁸: H; F; Cl; CF₃; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵        (where R⁵⁵: lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶        (where R⁵⁶: lower alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴        (where R³³: lower alkyl; or lower alkenyl; R³⁴: H; or lower        alkyl; or R³³ and R³⁴ taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)OCONR³³R⁷⁵ (where R³³: H; or        lower alkyl; or lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl;        R³³: H; or lower alkyl; or lower alkenyl; R⁸²: H; or lower        alkyl; or R³³ and R² taken together form: —(CH₂)₂₋₆—;        —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where        R⁵⁷: H; or lower alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H;        or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; or lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower alkenyl);        —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower alkenyl); or        —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R²⁰: H; or lower alkyl.    -   R³⁰: H, methyl.    -   R³¹: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); (—CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy); most preferred is        —CH₂CONR⁵⁸R⁵⁹ (R⁵⁸: H; or lower alkyl; R⁵⁹: lower alkyl; or        lower alkenyl).    -   R³²: H, methyl.    -   R³³: lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³⁴R⁶³ (where R³⁴:        lower alkyl; or lower alkenyl; R⁶³: H; or lower alkyl; or R³⁴        and R⁶³ taken together form: —(CH₂)₂₋₆—; —CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); (CH₂)_(m)OCONR⁷⁵R³²(where R⁷⁵: lower alkyl; or lower        alkenyl; R⁸²: H; or lower alkyl; or R⁷⁵ and R⁸² taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR⁷⁸R⁸² (where R²⁰: H; or lower alkyl; R⁷⁸: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R⁷⁸        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl).    -   R³⁴: H; or lower alkyl.    -   R³⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰OCONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)NN(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl).    -   R³⁶: lower alkyl; lower alkenyl; or aryl-lower alkyl.    -   R³⁷: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)N³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)OR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵¹R⁵⁹ (where        R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alky, or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R³⁸: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁸ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR¹⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶⁰)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R³⁹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where:        R²⁰: H; or lower alkyl; R⁶⁴: lower alkyl; or lower alkenyl);        —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl; or lower alkenyl);        —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵⁸: lower alkyl; or lower alkenyl;        and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken together form:        —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl).    -   R⁴⁰: lower alkyl; lower alkenyl; or aryl-lower alkyl.    -   R⁴¹: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)N³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₄—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR¹⁸R¹⁹ (where        R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alky; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R⁴²: H; lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl, or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)PO(OR⁶)₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)₀SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R⁴³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR¹⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₄—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)OPO(OR⁶¹ ₂ (where R⁶⁰: lower alkyl; or lower        alkenyl); —(CH₂)_(o)SO₂R⁶² (where R⁶²: lower alkyl; or lower        alkenyl); or —(CH₂)_(q)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R⁴⁴: lower alkyl; lower alkenyl; —(CH₂)_(p)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(p)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(p)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁸ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(p)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₄—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(p)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(p)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); or —(CH₂)₀C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl;        lower alkenyl; or lower alkoxy).    -   R⁴⁵: H; lower alkyl; lower alkenyl; —(CH₂)_(o)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(o)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(o)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(s)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(o)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₄—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(o)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); or —(CH₂)₅C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl;        lower alkenyl; or lower alkoxy).    -   R⁴⁶: H; lower alkyl; lower alkenyl; —(CH₂)_(s)OR⁵⁵ (where R⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(s)SR⁵⁶ (where R⁵⁶: lower        alkyl; or lower alkenyl); —(CH₂)_(s)NR³³R³⁴ (where R³³: lower        alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³ and R³⁴        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(s)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(s)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₄—; —(CH₂)₂O(CH₂)—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(s)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(o)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(o)CONR⁵³R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); or —(CH₂)_(s)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R⁴⁷: H; or OR⁵⁵ (where R⁵⁵: lower alkyl; or lower alkenyl).    -   R⁴⁸: H; or lower alkyl.    -   R⁴⁹: H; lower alkyl; —(CH₂)_(o)COOR⁵⁷ (where R⁵⁷: lower alkyl;        or lower alkenyl); —(CH₂)_(o)CONR⁵⁸R⁵⁹ (where R⁵s: lower alkyl;        or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹ taken        together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl); or        (CH₂)_(s)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower alkyl; lower        alkenyl; or lower alkoxy).    -   R⁵⁰: H; methyl.    -   R⁵¹: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); (CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R¹⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)R²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H; or        lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(p)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); or —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R⁵²: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower allyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)_(r); or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl; R⁶⁴: lower        alkyl; or lower alkenyl); —(CH₂)_(p)COOR⁵⁷ (where R⁵⁷: lower        alkyl; or lower alkenyl); —(CH₂)_(p)CONR⁵¹R⁵⁹ (where R⁵⁸: lower        alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or R⁵⁸ and R⁵⁹        taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); or —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R⁵³: H; lower alkyl; lower alkenyl; —(CH₂)_(m)OR⁵⁵ (where R⁵⁵:        lower alkyl; or lower alkenyl); —(CH₂)_(m)NR³³R³⁴ (where R³³:        lower alkyl; or lower alkenyl; R³⁴: H; or lower alkyl; or R³³        and R³⁴ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)OCONR³³R⁷⁵ (where R³³: H; or lower alkyl; or        lower alkenyl; R⁷⁵: lower alkyl; or R³³ and R⁷⁵ taken together        form: —(CH₂)₂₆—; —(CH₂)₂O(CH₂)₂—; —(CH₂)₂S(CH₂)₂—; or        —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower alkyl);        —(CH₂)_(m)NR²⁰CONR³³R⁸² (where R²⁰: H; or lower alkyl; R³³: H;        or lower alkyl; or lower alkenyl; R⁸²: H; or lower alkyl; or R³³        and R⁸² taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); —(CH₂)_(m)N(R²⁰)COR⁶⁴ (where: R²⁰: H; or lower alkyl;        R⁶⁴: lower alkyl; or lower alkenyl); —(CH₂)_(p)COOR⁵⁷ (where        R⁵⁷: lower alkyl; or lower alkenyl); —(CH₂)_(p)CONR⁵⁸R⁵⁹ (where        R⁵⁸: lower alkyl; or lower alkenyl; and R⁵⁹: H; lower alkyl; or        R⁵⁸ and R⁵⁹ taken together form: —(CH₂)₂₋₆—; —(CH₂)₂O(CH₂)₂—;        —(CH₂)₂S(CH₂)₂—; or —(CH₂)₂NR⁵⁷(CH₂)₂—; where R⁵⁷: H; or lower        alkyl); or —(CH₂)_(r)C₆H₄R⁸ (where R⁸: H; F; Cl; CF₃; lower        alkyl; lower alkenyl; or lower alkoxy).    -   R⁵⁴: lower alkyl; lower alkenyl; or aryl-lower alkyl.

Among the building blocks A70 to A104 the following are preferred: A74with R²² being H, A75, A76, A77 with R²² being H, A78 and A79.

The building block —B—CO— within template (a1) through (a4) designatesan L-amino acid residue. Preferred values for B are: —NR²⁰CH(R⁷¹)— andenantiomers of groups A5 with R² being H, A8, A22, A25, A38 with R²being H, A42, A47, and A50. Most preferred are

Asn L-Asparagine Cys L-Cysteine Gln L-Glutamine His L-Histidine MetL-Methionine Phe L-Phenylalanine Pro L-Proline Ser L-Serine ThrL-Threonine Trp L-Tryptophan Tyr L-Tyrosine Sar Sarcosine 4AmPheL-para-Aminophenylalanine 3AmPhe L-meta-Aminophenylalanine 2AmPheL-ortho-Aminophenylalanine Phe(mC(NH₂)═NH) L-meta-AmidinophenylalaninePhe(pC(NH₂)═NH) L-para-Amidinophenylalanine Phe(mNHC (NH₂)═NH)L-meta-Guanidinophenylalanine Phe(pNHC (NH₂)═NH)L-para-Guanidinophenylalanine Phg L-Phenylglycine ChaL-Cyclohexylalanine C₄al L-3-Cyclobutylalanine C₅alL-3-Cyclopentylalanine 2-Nal L-2-Naphthylalanine 1-NalL-1-Naphthylalanine 4Cl-Phe L-4-Chlorophenylalanine 3Cl-PheL-3-Chlorophenylalanine 2Cl-Phe L-2-Chlorophenylalanine 3,4Cl₂-PheL-3,4-Dichlorophenylalanine 4F-Phe L-4-Fluorophenylalanine 3F-PheL-3-Fluorophenylalanine 2F-Phe L-2-Fluorophenylalanine TicL-1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid ThiL-β-2-Thienylalanine Tza L-2-Thiazolylalanine Mso L-Methionine sulfoxideY(Bzl) L-O-Benzyltyrosine Bip L-Biphenylalanine S(Bzl) L-O-BenzylserineT(Bzl) L-O-Benzylthreonine hCha L-Homo-cyclohexylalanine hCysL-Homo-cysteine hSer L-Homo-serine hPhe L-Homo-phenylalanine BpaL-4-Benzoylphenylalanine Pip L-Pipecolic acid OctG L-Octylglycine MePheL-N-Methylphenylalanine MeNle L-N-Methylnorleucine MeAlaL-N-Methylalanine MeIle L-N-Methylisoleucine MeVal L-N-Methvaline MeLeuL-N-Methylleucine

In template (a4), an additional preferred value for the building block—B—CO— is

AMPA 3-Aminomethyphenyl acetic acid

In addition, the most preferred values for B also include groups of typeA8″ of (L)-configuration:

wherein R²⁰ is H or lower alkyl and R⁶⁴ is alkyl; alkenyl; aryl;aryl-lower alkyl; or heteroaryl-lower alkyl; especially those whereinR⁶⁴ is n-hexyl (A8″-21); n-heptyl (A8″-22); 4-(phenyl)benzyl (A8″-23);diphenylmethyl (A8″-24); 3-amino-propyl (A8″-25); 5-amino-pentyl(A8″-26); methyl (A8″-27); ethyl (A8″-28); isopropyl (A8″-29); isobutyl(A8″-30); n-propyl (A8″-31); cyclohexyl (A8″-32); cyclohexylmethyl(A8″-33); n-butyl (A8″-34); phenyl (A8″-35); benzyl (A8″-36);(3-indolyl)methyl (A8″-37); 2-(3-indolyl)ethyl (A8″-38);(4-phenyl)phenyl (A8″-39); and n-nonyl (A8″-40).

The peptidic chains Z and Z¹ of the β-hairpin mimetics described hereinare generally defined in terms of amino acid residues belonging to oneof the following groups:

-   -   Group C —NR²⁰CH(R⁷²)CO—; “hydrophobic: small to medium-sized”    -   Group D —NR²⁰CH(R⁷³)CO—; “hydrophobic: large aromatic or        heteroaromatic”    -   Group E —NR²⁰CH(R⁷⁴)CO—; “polar-cationic” and “urea-derived”    -   Group F —NR²⁰CH(R⁸⁴)CO—; “polar-non-charged”    -   Group H —NR²⁰—CH(CO—)—(CH₂)₄₋₇—CH(CO—)—NR²⁰—;        —NR²⁰—CH(CO—)—(CH₂)_(p)SS(CH₂)_(p)—CH(CO—)—NR²⁰—;        —NR²⁰—CH(CO—)—(—(CH₂)_(p)NR²⁰CO(CH₂)_(p)—CH(CO—)—NR²⁰—; and        —NR²⁰—CH(CO—)—(—(CH₂)_(p)NR²⁰CONR²⁰(CH₂)_(p)—CH(CO—)—NR²⁰—;        “interstrand linkage”    -   Group I —NR⁸⁶CH₂CO—; “polar-cationic”

Furthermore, Gly can also be an amino acid residue in chains Z and Z¹,and Pro can be an amino acid residue in chains Z and Z¹, too, with theexception of positions where interstrand linkages (H) are possible.

Group C comprises amino acid residues with small to medium-sizedhydrophobic side chain groups according to the general definition forsubstituent R⁷². A hydrophobic residue refers to an amino acid sidechain that is uncharged at physiological pH and that is repelled byaqueous solution. Furthermore these side chains generally do not containhydrogen bond donor groups, such as (but not limited to) primary andsecondary amides, primary and secondary amines and the correspondingprotonated salts thereof, thiols, alcohols, phosphonates, phosphates,ureas or thioureas. However, they may contain hydrogen bond acceptorgroups such as ethers, thioethers, esters, tertiary amides, alkyl- oraryl phosphonates and phosphates or tertiary amines. Genetically encodedsmall-to-medium-sized amino acids include alanine, isoleucine, leucine,methionine and valine.

Group D comprises amino acid residues with aromatic and heteroaromaticside chain groups according to the general definition for substituentR⁷³. An aromatic amino acid residue refers to a hydrophobic amino acidhaving a side chain containing at least one ring having a conjugatedπ-electron system (aromatic group). In addition they may containhydrogen bond donor groups such as (but not limited to) primary andsecondary amides, primary and secondary amines and the correspondingprotonated salts thereof, thiols, alcohols, phosphonates, phosphates,ureas or thioureas, and hydrogen bond acceptor groups such as (but notlimited to) ethers, thioethers, esters, tetriary amides, alkyl- or arylphosphonates- and phosphates or tertiary amines. Genetically encodedaromatic amino acids include phenylalanine and tyrosine.

A heteroaromatic amino acid residue refers to a hydrophobic amino acidhaving a side chain containing at least one ring having a conjugatedn-system incorporating at least one heteroatom such as (but not limitedto) O, S and N according to the general definition for substituent R⁷⁷.In addition such residues may contain hydrogen bond donor groups such as(but not limited to) primary and secondary amides, primary and secondaryamines and the corresponding protonated salts thereof, thiols, alcohols,phosphonates, phosphates, ureas or thioureas, and hydrogen bond acceptorgroups such as (but not limited to) ethers, thioethers, esters, tetriaryamides, alkyl- or aryl phosphonates- and phosphates or tertiary amines.Genetically encoded heteroaromatic amino acids include tryptophan andhistidine.

Group E comprises amino acids containing side chains withpolar-cationic, acylamino- and urea-derived residues according to thegeneral definition for substituen R⁷⁴. Polar-cationic refers to a basicside chain which is protonated at physiological pH. Genetically encodedpolar-cationic amino acids include arginine, lysine and histidine.Citrulline is an example for an urea derived amino acid residue.

Group F comprises amino acids containing side chains withpolar-non-charged residues according to the general definition forsubstituent R⁸⁴. A polar-non-charged residue refers to a hydrophilicside chain that is uncharged at physiological pH, but that is notrepelled by aqueous solutions. Such side chains typically containhydrogen bond donor groups such as (but not limited to) primary andsecondary amides, primary and secondary amines, thiols, alcohols,phosphonates, phosphates, ureas or thioureas. These groups can formhydrogen bond networks with water molecules. In addition they may alsocontain hydrogen bond acceptor groups such as (but not limited to)ethers, thioethers, esters, tetriary amides, alkyl- or arylphosphonates- and phosphates or tertiary amines. Genetically encodedpolar-non-charged amino acids include asparagine, cysteine, glutamine,serine and threonine.

Group H comprises side chains of preferably (L)-amino acids at oppositepositions of the β-strand region that can form an interstrand linkage.The most widely known linkage is the disulfide bridge formed bycysteines and homo-cysteines positioned at opposite positions of theβ-strand. Various methods are known to form disulfide linkages includingthose described by: J. P. Tam et al. Synthesis 1979, 955-957; Stewart etal., Solid Phase Peptide Synthesis, 2d Ed., Pierce Chemnical Company,III., 1984; Ahmed et al. J. Biol. Chem. 1975, 250, 8477-8482; andPennington et al., Peptides, pages 164-166, Giralt and Andreu, Eds.,ESCOM Leiden, The Netherlands, 1990. Most advantageously, for the scopeof the present invention, disulfide linkages can be prepared usingacetamidomethyl (Acm)-protective groups for cysteine. A well establishedinterstrand linkage consists in linking ornithines and lysines,respectively, with glutamic and aspartic acid residues located atopposite β-strand positions by means of an amide bond formation.Preferred protective groups for the side chain amino-groups of ornithineand lysine are allyloxycarbonyl (Alloc) and allylesters for aspartic andglutamic acid. Finally, interstrand linkages can also be established bylinking the amino groups of lysine and ornithine located at oppositeβ-strand positions with reagents such as N,N-carbonylimidazole to formcyclic ureas.

Group I comprises glycine having the amino group substituted by chainscontaining polar-cationic residues according to the general definitionfor substituent R⁸⁶. Polar-cationic refers to a basic side chain whichis protonated at physiological pH.

As mentioned earlier, positions for interstrand linkages are thefollowing:

-   If n is 4 and n′ is 6 Postitions P3 and P3′ taken together-   If n is 5 and n′ is 7 Postitions P2 and P2′ and/or P4 and P4′, taken    together

Such interstrand linkages are known to stabilize the β-hairpinconformations and thus constitute an important structural element forthe design of β-hairpin mimetics.

Most preferred amino acid residues in chains Z and Z¹ are those derivedfrom natural α-amino acids. Hereinafter follows a list of amino acidswhich, or the residues of which, are suitable for the purposes of thepresent invention, the abbreviations corresponding to generally adoptedusual practice:

three letter code one letter code Ala L-Alanine A Arg L-Arginine R AsnL-Asparagine N Asp L-Aspartic acid D Cys L-Cysteine C Glu L-Glutamicacid E Gln L-Glutamine Q Gly Glycine G His L-Histidine H IleL-Isoleucine I Leu L-Leucine L Lys L-Lysine K Met L-Methionine M PheL-Phenylalanine F Pro L-Proline P ^(D)Pro D-Proline ^(D)P Ser L-Serine SThr L-Threonine T Trp L-Tryptophan W Tyr L-Tyrosine Y Val L-Valine V

Other α-amino acids which, or the residues of which, are suitable forthe purposes of the present invention include:

Cit L-Citrulline Orn L-Ornithine tBuA L-t-Butylalanine Sar Sarcosine PenL-Penicillamine t-BuG L-tert.-Butylglycine 4AmPheL-para-Aminophenylalanine 3AmPhe L-meta-Aminophenylalanine 2AmPheL-ortho-Aminophenylalanine Phe(mC(NH₂)═NH) L-meta-AmidinophenylalaninePhe(pC(NH₂)═NH) L-para-Amidinophenylalanine Phe(mNHC (NH₂)═NH)L-meta-Guanidinophenylalanine Phe(pNHC (NH₂)═NH)L-para-Guanidinophenylalanine Phg L-Phenylglycine ChaL-Cyclohexylalanine C₄al L-3-Cyclobutylalanine C₅alL-3-Cyclopentylalanine Nle L-Norleucine 2-Nal L-2-Naphthylalanine 1-NalL-1-Naphthylalanine 4Cl-Phe L-4-Chlorophenylalanine 3Cl-PheL-3-Chlorophenylalanine 2Cl-Phe L-2-Chlorophenylalanine 3,4Cl₂-PheL-3,4-Dichlorophenylalanine 4F-Phe L-4-Fluorophenylalanine 3F-PheL-3-Fluorophenylalanine 2F-Phe L-2-Fluorophenylalanine Tic1,2,3,4-Tetrahydroisoquinoline-3-carboxylic acid ThiL-β-2-Thienylalanine Tza L-2-Thiazolylalanine Mso L-Methionine sulfoxideAcLys N-Acetyllysine Dpr 2,3-Diaminopropionic acid A₂Bu2,4-Diaminobutyric acid Dbu (S)-2,3-Diaminobutyric acid Abuγ-Aminobutyric acid (GABA) Aha ε-Aminohexanoic acid Aibα-Aminoisobutyric acid Y(Bzl) L-O-Benzyltyrosine BipL-(4-phenyl)phenylalanine S(Bzl) L-O-Benzylserine T(Bzl)L-O-Benzylthreonine hCha L-Homo-cyclohexylalanine hCys L-Homo-cysteinehSer L-Homo-serine hArg L-Homo-arginine hPhe L-Homo-phenylalanine BpaL-4-Benzoylphenylalanine 4-AmPyrr1(2S,4S)-4-Amino-pyrrolidine-L-carboxylic acid 4-AmPyrr2(2S,4R)-4-Amino-pyrrolidine-L-carboxylic acid 4-PhePyrr1(2S,5R)-4-Phenyl-pyrrolidine-L-carboxylic acid 4-PhePyrr2(2S,5S)-4-Phenyl-pyrrolidine-L-carboxylic acid 5-PhePyrr1(2S,5R)-5-Phenyl-pyrrolidine-L-carboxylic acid 5-PhePyrr2(2S,5S)-5-Phenyl-pyrrolidine-L-carboxylic acid Pro(4-OH)1(4S)-L-Hydroxyproline Pro(4-OH)2 (4R)-L-Hydroxyproline Pip L-Pipecolicacid ^(D)Pip D-Pipecolic acid OctG L-Octylglycine MePheL-N-Methylphenylalanine MeNle L-N-Methylnorleucine MeAlaL-N-Methylalanine MeIle L-N-Methylisoleucine MeVal L-N-MethylvalineMeLeu L-N-Methylleucine W(6-Cl) L-6-Cl-Tryptophan (EA)GN-(2-Aminoethyl)glycine (PrA)G N-(3-Amino-n-propyl)glycine (BA)GN-(4-Amino-n-butyl)glycine (PeA)G N-(5-Amino-n-pentyl)glycine (EGU)GN-(2-Guanidinoethyl)glycine (PrGU)G N-(3-Guanidino-n-propyl)glycine(BGU)G N-(4-Guanidino-n-butyl)glycine (PeGU)GN-(5-Guanidino-n-pentyl)glycine (PEG₃-NH₂)GN—[(CH₂)₃O—(CH₂—CH₂O)₂—(CH₂)₃—NH₂]glycine

Particularly preferred residues for group C are:

Ala L-Alanine Ile L-Isoleucine Leu L-Leucine Met L-Methionine ValL-Valine tBuA L-t-Butylalanine t-BuG L-tert.-Butylglycine ChaL-Cyclohexylalanine C₄al L-3-Cyclobutylalanine C₅alL-3-Cyclopentylalanine Nle L-Norleucine hCha L-Homo-cyclohexylalanineOctG L-Octylglycine MePhe L-N-Methylphenylalanine MeNleL-N-Methylnorleucine MeAla L-N-Methylalanine MeIle L-N-MethylisoleucineMeVal L-N-Methylvaline MeLeu L-N-Methylleucine

Particularly preferred residues for group D are:

His L-Histidine Phe L-Phenylalanine Trp L-Tryptophan Tyr L-Tyrosine PhgL-Phenylglycine 2-Nal L-2-Naphthylalanine 1-Nal L-1-Naphthylalanine4Cl-Phe L-4-Chlorophenylalanine 3Cl-Phe L-3-Chlorophenylalanine 2Cl-PheL-2-Chlorophenylalanine 3,4Cl₂-Phe L-3,4-Dichlorophenylalanine 4F-PheL-4-Fluorophenylalanine 3F-Phe L-3-Fluorophenylalanine 2F-PheL-2-Fluorophenylalanine Thi L-β-2-Thienylalanine TzaL-2-Thiazolylalanine Y(Bzl) L-O-Benzyltyrosine Bip L-BiphenylalanineS(Bzl) L-O-Benzylserine T(Bzl) L-O-Benzylthreonine hPheL-Homo-phenylalanine Bpa L-4-Benzoylphenylalanine W(6-Cl)L-6-Cl-Tryptophan

Particularly preferred residues for group E are

Arg L-Arginine Lys L-Lysine Orn L-Ornithine Dpr L-2,3-Diaminopropionicacid A₂Bu L-2,4-Diaminobutyric acid Dbu (S)-2,3-Diaminobutyric acidF(pNH₂) L-para-Aminophenylalanine Phe(mNH₂) L-meta-AminophenylalaninePhe(oNH₂) L-ortho-Aminophenylalanine hArg L-Homo-argininePhe(mC(NH₂)═NH) L-meta-Amidinophenylalanine Phe(pC(NH₂)═NH)L-para-Amidinophenylalanine Phe(mNHC (NH₂)═NH)L-meta-Guanidinophenylalanine Phe(pNHC (NH₂)═NH)L-para-Guanidinophenylalanine

Particularly preferred residues for group F are

Asn L-Asparagine Cys L-Cysteine Gln L-Glutamine Ser L-Serine ThrL-Threonine Cit L-Citrulline Pen L-Penicillamine AcLysL-N^(ε)-Acetyllysine hCys L-Homo-cysteine hSer L-Homo-serine

Particularly preferred residues for group I are

(EA)G N-(2-Aminoethyl)glycine (PrA)G N-(3-Amino-n-propyl)glycine (BA)GN-(4-Amino-n-butyl)glycine (PeA)G N-(5-Amino-n-pentyl)glycine (EGU)GN-(2-Guanidinoethyl)glycine (PrGU)G N-(3-Guanidino-n-propyl)glycine(BGU)G N-(4-Guanidino-n-butyl)glycine (PeGU)GN-(5-Guanidino-n-pentyl)glycine (PEG₃-NH₂)GN—[(CH₂)₃O—(CH₂—CH₂O)₂—(CH₂)₃—NH₂]glycine

As mentioned earlier, the peptidic chains Z and Z¹ within the β-hairpinmimetics of the invention comprise 4 and, respectively, 6 residues or 5and, respectively, 7 residues. The positions P¹ to P^(n) and P^(1′) toP^(n′) of each amino acid residue in the chain Z and, respectively, Z¹are unequivocally defined as follows: P¹ represents the first amino acidin the chain Z that is coupled with its C-terminus to the N-terminus ofthe templates (b)-(p) or of group —B— CO— in templates (a1), (a3) or(a4) or of group -A-CO— in template (a2), and P^(n) represents the lastamino acid in the chain Z; P^(1′) represents the first amino acid in thechain Z¹ that is coupled with its N-terminus to the C-terminus of thecorresponding templates (b)-(p) or of group —B—CO— in template (a1),(a3) or (a4) or of group -A-CO— in template (a2), and P^(n′) representsthe last amino acid in the chain Z¹.

Each of the positions P¹ to P^(n) or P^(1′) to P^(n′) will preferablycontain an amino acid residue belonging to one or two or three of theabove types C, D, E, F I, or being Pro or Gly, as follows:

If n is 4 and n′ is 6, the amino acid residues in positions 1 to 4 of Zand the amino acid residues in positions 1′ to 6′ of Z¹ are preferably:

-   -   P1: of type D or of type E or of type F, or the residue is Pro;    -   P2: of type E or of type F;    -   P3: of type F, or the residue is Pro;    -   P4: of type E;    -   P1′: of type E or of type F, or the residue is Gly;    -   P2′: of type D;    -   P3′: of type F or the residue is Pro;    -   P4′: of type D;    -   P5′: of type E, or of type F or the residue is Pro; and    -   P6′: of type E or of type F, or the residue is Pro; or    -   P3 and P3′, taken together, can form a group of type H.

If n is 5 and n′ is 7, the amino acid residues in positions 1 to 5 of Zand the amino acid residues in positions 1′ to 7′ of Z¹ are preferably:

-   -   P1: of type D or of type E or of type F, or the residue is Pro;    -   P2: of type E or of type F;    -   P3: of type F, or the residue is Pro;    -   P4: of type F;    -   P5: of type E    -   P1′: of type D or of type E or of type F, or the residue is Pro;    -   P2′: of type F;    -   P3′: of type D or the residue is Pro;    -   P4′: of type F;    -   P5′: of type D, or the residue is Pro;    -   P6′: of type E or of type F, or the residue is Pro; and    -   P7′: of type E or of type I, or the residue is Gly; or    -   P2 and P2′ and/or P4 and P4′, taken together, can form a group        of type H; at P7′ also D-isomers being possible.

If n is 4 and n′ is 6, the amino acid residues in positions 1 to 4 of Zand the amino acid residues in positions 1′ to 6′ of Z¹ are mostpreferably:

-   -   P1: Tyr, Arg;    -   P2: Cit, Arg;    -   P3: Cys;    -   P4: Arg-NH₂;    -   P1′: Lys, Arg;    -   P2′: Tyr;    -   P3′: Cys;    -   P4′: 2-Nal;    -   P5′: Arg; and    -   P6′: Arg.        -   Cys at pos P3 and P3′ form a disulfide bridge

If n is 5 and n′ is 7, the amino acid residues in positions 1 to 5 of Zand the amino acid residues in positions 1′ to 7′ of Z¹ are mostpreferably:

-   -   P1: Tyr;    -   P2: Arg;    -   P3: Cit;    -   P4: Cys;    -   P5: Arg; Arg-NH₂;    -   P1′: Lys;    -   P2′: Cit;    -   P3′: Tyr;    -   P4′: Cys;    -   P5′: 2-Nal, Trp, F(pNH₂), W(6-Cl);    -   P6′: Arg; and    -   P7′: ^(D)Arg, Arg, Ac-Arg, iPr-Arg, (EA)G, (PrA)G, (BA)G,        (EGU)G, (PrGU)G, (BGU)G.        -   Cys at pos 4 and pos 4′ form a disulfide bridge

Particularly preferred β-peptidomimetics of the invention include thosedescribed in Examples 6, 7, 8, 10, 12, 15, 20, 21, 22.

The process of the invention can advantageously be carried out asparallel array synthesis to yield libraries of template-fixed β-hairpinpeptidomimetics of the above general formula I. Such parallel synthesisallows one to obtain arrays of numerous (normally 24 to 192, typically96) compounds of general formula I in high yields and defined purities,minimizing the formation of dimeric and polymeric by-products. Theproper choice of the functionalized solid-support (i.e. solid supportplus linker molecule), and the templates play thereby key roles.

The functionalized solid support is conveniently derived frompolystyrene crosslinked with, preferably 1-5%, divinylbenzene;polystyrene coated with polyethyleneglycol spacers (Tentagel^(R)); andpolyacrylamide resins (see also Obrecht, D.; Villalgordo, J.-M,“Solid-Supported Combinatorial and Parallel Synthesis ofSmall-Molecular-Weight Compound Libraries”, Tetrahedron OrganicChemistry Series, Vol. 17, Pergamon, Elsevier Science, 1998).

The solid support is functionalized by means of a linker, i.e. abifunctional spacer molecule which contains on one end an anchoringgroup for attachment to the solid support and on the other end aselectively cleavable functional group used for the subsequent chemicaltransformations and cleavage procedures. For the purposes of the presentinvention two types of linkers are used:

Type 1 linkers are designed to release the amide group under acidconditions (Rink H, Tetrahedron Leut. 1987, 28, 3783-3790). Linkers osthis kind form amides of the carboxyl group of the amino acids; examplesof resins functionalized by such linker structures include4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido)aminomethyl] PS resin,4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido)aminomethyl]-4-methylbenzydrylamine PS resin (Rink amide MBHA PS Resin),and 4-[(((2,4-dimethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido)aminomethyl] benzhydrylamine PS-resin (Rink amide BHA PS resin).Preferably, the support is derived from polystyrene crosslinked with,most preferably 1-5%, divinylbenzene and functionalized by means of the4-(((2,4-imethoxyphenyl)Fmoc-aminomethyl)phenoxyacetamido) linker.

Type 2 linkers are designed to eventually release the carboxyl groupunder acidic conditions. Linkers of this kind form acid-labile esterswith the carboxyl group of the amino acids, usually acid-labile benzyl,benzhydryl and trityl esters; examples of such linker structures include2-methoxy-4-hydroxymethylphenoxy (Sasrin^(R) linker),4-(2,4-dimethoxyphenyl-hydroxymethyl)-phenoxy (Rink linker),4-(4-hydroxymethyl-3-methoxyphenoxy)butyric acid (HMPB linker), trityland 2-chlorotrityl. Preferably, the support is derived from polystyrenecrosslinked with, most preferably 1-5%, divinylbenzene andfunctionalized by means of the 2-chlorotrityl linker.

When carried out as a parallel array synthesis the process of theinvention can be advantageously carried out as described hereinbelow butit will be immediately apparent to those skilled in the art how theseprocedures will have to be modified in case it is desired to synthesizeone single compound of the above formula I

A number of reaction vessels (normally 24 to 192, typically 96) equal tothe total number of compounds to be synthesized by the parallel methodare loaded with 25 to 1000 mg, preferably 100 mg, of the appropriatefunctionalized solid support, preferably 1 to 3% cross linkedpolystyrene.

The solvent to be used must be capable of swelling the resin andincludes, but is not limited to, dichloromethane (DCM),dimethylformarnmide (DMF), N-methylpyrrolidone (NM), dioxane, toluene,tetrahydrofuran (THF), ethanol (EtOH), trifluoroethanol (TFE),isopropylalcohol and the like. Solvent mixtures containing as at leastone component a polar solvent (e.g. 20% TFE/DCM, 35% THF/NMP) arebeneficial for ensuring high reactivity and solvation of the resin-boundpeptide chains (Fields, G. B., Fields, C. G., J. Am. Chem. Soc. 1991,113, 4202-4207).

Both the Rink linker that releases the C-terminal carboxylic amide groupunder acidic conditions and the 2-chlorotrityl linker that releases theC-termiinal carboxylic acid group under acidic conditions, are stable toFmoc deprotection conditions during the peptide synthesis.

The simultaneous release of the side chain protecting groups of thepeptide fragment and the release of the peptide from the resin type Iand type 2 is performed with 95% TFA and dichloromethane and scavencerssuch as phenol or triisopropylsilane (Bematowicz, S. B. et al,Tetrahedron Lett., 1989, 30, 4645-4648).

Suitable protecting groups for amino acids and, respectively, for theirresidues are, for example,

-   -   for the amino group (as is present e.g. also in the side-chain        of lysine)

Cbz benzyloxycarbonyl Boc tert.-butyloxycarbonyl Fmoc9-fluorenylmethoxycarbonyl Alloc allyloxycarbonyl Teoctrimethylsilylethoxycarbonyl Tcc trichloroethoxycarbonyl Npso-nitrophenylsulfonyl; Trt triphenymethyl or trityl

-   -   for the carboxyl group (as is present e.g. also in the        side-chain of aspartic and glutarnic acid) by conversion into        esters with the alcohol components

tBu tert.-butyl Bn benzyl Me methyl Ph phenyl Pac Phenacyl Allyl Tsetrimethylsilylethyl Tce trichloroethyl;

-   -   for the guanidino group (as is present e.g. in the side-chain of        arginine)

Pmc 2,2,5,7,8-pentamethylchroman-6-sulfonyl Ts tosyl (i.e.p-toluenesulfonyl) Cbz benzyloxycarbonyl Pbfpentamethyldihydrobenzofuran-5-sulfonyl

-   -   for the hydroxy group (as is present e.g. in the side-chain of        threonine and serine)

tBu tert.-butyl Bn benzyl Trt trityl

-   -   and for the mercapto group (as is present e.g. in the side-chain        of cysteine)

Acm acetamidomethyl tBu tert.-butyl Bn benzyl Trt trityl Mtr4-methoxytrityl.

The 9-fluorenylmethoxycarbonyl-(Fmoc)-protected amino acid derivativesare preferably used as the building blocks for the construction of thetemplate-fixed β-hairpin loop mimetics of formula I. For thedeprotection, i.e. cleaving off of the Fmoc group, 20% piperidine in DMFor 2% DBU/2% piperidine in DMF can be used.

N-substituted glycine derivatives (type I) used as building blocks forthe construction of certain compounds of formula I are derived from9-fluorenylmethoxycarbonyl-(Fmoc)-protected amino acid derivatives oralternatively built up in two steps from leaving group-containingglycine precursors, such as bromo, chloro or iodo acetic acid, andsuitable primary amine building blocks NH₂—R⁸⁶. The first synthesis stepconsists of the attachment of the leaving group-containing acetylatingagent, such as bromo acetic acid, to the resin bound intermediatethrough formation of the amide bond. The second reaction step—thenucleophilic displacement—is accomplished using the primary aminebuilding blocks, wherein the residues are, if necessary, suitablyprotected with groups as described above for side chains of amino acids.

The quantity of the reactant, i.e. of the amino acid derivative, isusually 1 to 20 equivalents based on the milliequivalents per gram(meq/g) loading of the functionalized solid support (typically 0.1 to2.85 meq/g for polystyrene resins) originally weighed into the reactiontube. Additional equivalents of reactants can be used if required todrive the reaction to completion in a reasonable time. The reactiontubes, in combination with the holder block and the manifold, arereinserted into the reservoir block and the apparatus is fastenedtogether. Gas flow through the manifold is initiated to provide acontrolled environment, for example, nitrogen, argon, air and the like.The gas flow may also be heated or chilled prior to flow through themanifold. Heating or cooling of the reaction wells is achieved byheating the reaction block or cooling externally with isopropanol/dryice and the like to bring about the desired synthetic reactions.Agitation is achieved by shaking or magnetic stirring (within thereaction tube). The preferred workstations (without, however, beinglimited thereto) are Labsource's Combi-chem station and MultiSynTech's-Syro synthesizer.

Amide bond formation requires the activation of the α-carboxyl group forthe acylation step. When this activation is being carried out by meansof the commonly used carbodjimides such as dicyclohexylcarbodiimide(DCC, Sheehan & Hess, J. Am. Chem. Soc. 1955, 77, 1067-1068) ordiisopropylcarbodiimide (DIC, Sarantakis et al Biochem. Biophys. Res.Commun. 1976, 73, 336-342), the resulting dicyclohexylurea is insolubleand, respectively, diisopropylurea is soluble in the solvents generallyused. In a variation of the carbodiimide method 1-hydroxybenzotriazole(HOBt, Kmnig & Geiger, Chem. Ber 1970, 103, 788-798) is included as anadditive to the coupling mixture. HOBt prevents dehydration, suppressesracemization of the activated amino acids and acts as a catalyst toimprove the sluggish coupling reactions. Certain phosphonium reagentshave been used as direct coupling reagents, such asbenzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP) (Castro et al., Tetrahedron Lett. 1975, 14,1219-1222; Synthesis, 1976, 751-752), orbenzotriazol-1-yl-oxy-tris-pyrrolidino-phosphonium hexaflurophoshate(Py-BOP, Coste et al., Tetrahedron Lett. 1990, 31, 205-208), or2-(1H-benzotriazol-1-yl-)1,1,3,3-tetramethyluronium terafluoroborate(TBTU), or hexafluorophosphate (HBTU, Knorr et al., Tetrahedron Lett.1989, 30, 1927-1930); these phosphonium reagents are also suitable forin situ formation of HOBt esters with the protected amino acidderivatives. More recently diphenoxyphosphoryl azide (DPPA) orO-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumtetrafluoroborate (TATU) orO-(7-aza-benzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU)/7-aza-1-hydroxy benzotriazole (HOAt, Carpinoet al., Tetrahedron Lett. 1994, 35, 2279-2281) have also been used ascoupling reagents.

Due to the fact that near-quantitative coupling reactions are essentialit is desirable to have experimental evidence for completion of thereactions. The ninhydrin test (Kaiser et al., Anal. Biochemistry 1970,34, 595), where a positive colorimetric response to an aliquot ofresin-bound peptide indicates qualitatively the presence of the primaryamine, can easily and quickly be performed after each coupling step.Fmoc chemistry allows the spectrophotometric detection of the Fmocchromophore when it is released with the base (Meienhofer et al., Int.J. Peptide Protein Res. 1979, 13, 3542).

The resin-bound intermediate within each reaction tube is washed free ofexcess of retained reagents, of solvents, and of by-products byrepetitive exposure to pure solvent(s) by one of the two followingmethods:

1) The reaction wells are filled with solvent (preferably 5 ml), thereaction tubes, in combination with the holder block and manifold, areimmersed and agitated for 5 to 300 minutes, preferably 15 minutes, anddrained by gravity followed by gas pressure applied through the manifoldinlet (while closing the outlet) to expel the solvent;

2) The manifold is removed from the holder block, aliquots of solvent(preferably 5 ml) are dispensed through the top of the reaction tubesand drained by gravity through a filter into a receiving vessel such asa test tube or vial.

Both of the above washing procedures are repeated up to about 50 times(preferably about 10 times), monitoring the efficiency of reagent,solvent, and byproduct removal by methods such as TLC, GC, or inspectionof the washings.

The above described procedure of reacting the resin-bound compound withreagents within the reaction wells followed by removal of excessreagents, by-products, and solvents is repeated with each successivetransformation until the final resin-bound fully protected linearpeptide has been obtained.

Before this fully protected linear peptide is detached from the solidsupport, it is possible, if desired, to selectively deprotect one orseveral protected functional group(s) present in the molecule and toappropriately substitute the reactive group(s) thus liberated. To thiseffect, the functional group(s) in question must initially be protectedby a protecting group which can be selectively removed without affectingthe remaining protecting groups present. Alloc (allyloxycarbonyl) is anexample for such a protecting group for amino which can be selectivelyremoved, e.g. by means of Pd° and phenylsilane in CH₂Cl₂, withoutaffecting the remaining protecting groups, such as Fmoc, present in themolecule. The reactive group thus liberated can then be treated with anagent suitable for introducing the desired substituent. Thus, forexample, an amino group can be acylated by means of an acylating agentcorresponding to the acyl substituent to be introduced.

Before detaching the peptide from the resin and removing the protectinggroups from the fully protected peptide, it is also possible, ifdesired, to cyclize the linear peptide by forming an interstrand linkagebetween side-chains of appropriate amino acid residues at oppositepositions of the β-strand region.

Interstrand linkages and their formation have been discussed above, inconnection with the explanations made regarding groups of the type Hwhich can, for example, be disulfide bridges formed by cysteines andhomocysteines at opposite positions of the β-strand, or glutamic andaspartic acid residues linking ornithines and, respectively, lysineslocated at opposite β-strand positions by amide bond formation. Theformation of such interstrand linkages can be effected by methods wellknown in the art. For the formation of disulfide bridges preferably asolution of 10 equivalents of iodine solution in DMF is applied for 1.5h. The procedure is repeated for another 3 h after with a fresh solutionafter filtering of the iodine solution.

Detachment and complete deprotection of the fully protected peptide fromthe solid support is achieved by immersion of the reaction tubes, incombination with the holder block and manifold, in reaction wellscontaining a solution of the cleavage reagent (preferably 3 to 5 ml).Gas flow, temperature control, agitation, and reaction monitoring areimplemented as described above and as desired to effect the detachmentreaction. The reaction tubes, in combination with the holder block andmanifold, are disassembled from the reservoir block and raised above thesolution level but below the upper lip of the reaction wells, and gaspressure is applied through the manifold inlet (while closing theoutlet) to efficiently expel the final product solution into thereservoir wells. The resin remaining in the reaction tubes is thenwashed 2 to 5 times as above with 3 to 5 ml of an appropriate solvent toextract (wash out) as much of the detached product as possible. Theproduct solutions thus obtained are combined, taking care to avoidcross-mixing. The individual solutions/extracts are then manipulated asneeded to isolate the final compounds. Typical manipulations include,but are not limited to, evaporation, concentration, liquid/liquidextraction, acidification, basification, neutralization or additionalreactions in solution.

Alternatively the detachment and complete deprotection of the fullyprotected peptide from the solid support is achieved manually in glassvessels.

The fully protected peptide derivative of type I is treated with 95%TFA, 2.5% H₂O, 2.5% TIS or another combination of scavengers foreffecting the cleavage of protecting groups. The cleavage reaction timeis commonly 30 minutes to 12 hours, preferably about 3.5 hours. Theresin is filtered and the cleavage solution containing the peptide isevaporated. The product is dissolved in an acid and water and extractedwith isopropyl ether or other solvents which are suitable therefor.After collecting the aqueous layer and optionally oxidizing bridges oftype H (Cysteine) by passing air through the aqueous layer and carefulremoval of the solvent, the cyclic peptide derivative obtained asend-product can be isolated. Depending on its purity, this peptidederivative can be used directly for biological assays, or it has to befurther purified, for example by preparative HPLC.

As mentioned earlier, it is thereafter possible, if desired, to converta fully deprotected product thus obtained into a pharmaceuticallyacceptable salt or to convert a pharmaceutically acceptable, orunacceptable, salt thus obtained into the corresponding free compound offormula I or into a different, pharmaceutically acceptable, salt. Any ofthese operations can be carried out by methods well known in the art.

The template starting materials of formula II used in the processes ofthe invention, pre-starting materials therefor, and the preparation ofthese starting and pre-starting materials are described in InternationalApplication PCT/EP02/01711 of the same applicants, published as WO02/070547 A1.

The starting materials of formula H₂NR⁸⁶ are known or can be prepared bymethods which are well known in the art.

The β-hairpin peptidomimetics of the invention can be used in a widerange of applications in order to prevent HIV infections in healthyindividuals and to slow or halt viral progression in infected patientsor to inhibit the growth of cancer cells or to treat inflammatorydisorders.

The β-hairpin peptidomimetics may-be administered per se or may beapplied as an appropriate formulations together with carriers, diluentsor excipients well known in the art.

When used to treat or prevent HIV infections or cancer the β-hairpinpeptidomimetics can be administered singly, as mixtures of severalβ-hairpin peptidomimetics, in combination with other anti-HIV agents, orantimicrobial agents or anti cancer agents, or in combination with otherpharmaceutically active agents. The β-hairpin peptidomimetics can beadministered per se or as pharmaceutical compositions.

Pharmaceutical compositions comprising β-hairpin peptidomimetics of theinvention may be manufactured by means of conventional mixing,dissolving, granulating, coated tablet-making, levigating, emulsifying,encapsulating, entrapping or lyophilizing processes. Pharmaceuticalcompositions may be formulated in conventional manner using one or morephysiologically acceptable carriers, diluents, excipients orauxilliaries which facilitate processing of the active β-hairpinpeptidomimetics into preparations which can be used pharmaceutically.Proper formulation depends upon the method of administration chosen.

For topical administration the β-hairpin peptidomimetics of theinvention may be formulated as solutions, gels, ointments, creams,suspensions, etc. as are well-known in the art

Systemic formulations include those designed for administration byinjection, e.g. subcutaneous, intravenous, intramuscular, intrathecal orintraperitoneal injection, as well as those designed for transdermal,transmucosal, oral or pulmonary administration.

For injections, the β-hairpin peptidomimetics of the invention may beformulated in adequate solutions, preferably in physiologicallycompatible buffers such as Hink's solution, Ringer's solution, orphysiological saline buffer. The solution may contain formulatory agentssuch as suspending, stabilizing and/or dispersing agents. Alternatively,the β-hairpin peptidomimetics of the invention may be in powder form forcombination with a suitable vehicle, e.g., sterile pyrogen-free water,before use.

For transmucosal administration, penetrants appropriate to the barrierto be permeated are used in the formulation as known in the art.

For oral administration, the compounds can be readily formulated bycombining the active β-hairpin peptidomimetics of the invention withpharmaceutically acceptable carriers well known in the art. Suchcarriers enable the β-hairpin peptidomimetics of the invention to beformulated as tablets, pills, dragees, capsules, liquids, gels, syrups,slurries, suspensions etc., for oral ingestion of a patient to betreated. For oral formulations such as, for example, powders, capsulesand tablets, suitable excipients include fillers such as sugars, such aslactose, sucrose, mannitol and sorbitol; cellulose preparations such asmaize starch, wheat starch, rice starch, potato starch, gelatin, gumtragacanth, methyl cellulose, hydroxypropylmethyl cellulose, sodiumcarboxymethylcellulose, and/or polyvinylpyrrolidone (PVP); granulatingagents; and binding agents. If desired, desintegrating agents may beadded, such as cross-linked polyvinylpyrrolidones, agar, or alginic acidor a salt thereof, such as sodium alginate. If desired, solid dosageforms may be sugar-coated or enteric-coated using standard techniques.

For oral liquid preparations such as, for example, suspensions, elixirsand solutions, suitable carriers, excipients or diluents include water,glycols, oils, alcohols, etc. In addition, flavoring agents,preservatives, coloring agents and the like may be added.

For buccal administration, the composition may take the form of tablets,lozenges, etc. formulated as usual.

For administration by inhalation, the β-hairpin peptidomimetics of theinvention are conveniently delivered in form of an aeorosol spray frompressurized packs or a nebulizer, with the use of a suitable propellant,e.g. dichlorodifluoromethane, trichlorofluromethane, carbon dioxide oranother suitable gas. In the case of a pressurized aerosol the dose unitmay be determined by providing a valve to deliver a metered amount.Capsules and cartridges of e.g. gelatin for use in an inhaler orinsufflator may be formulated containing a powder mix of the β-hairpinpeptidomimetics of the invention and a suitable powder base such aslactose or starch.

The compounds may also be formulated in rectal or vaginal compositionssuch as suppositories together with appropriate suppository bases suchas cocoa butter or other glycerides.

In addition to the formulations described previously, the β-hairpinpeptidomimetics of the invention may also be formulated as depotpreparations. Such long acting formulations may be administered byimplantation (e.g. subcutaneously or intramuscularly) or byintramuscular injection. For the manufacture of such depot preparationsthe β-hairpin peptidomimetics of the invention may be formulated withsuitable polymeric or hydrophobic materials (e.g. as an emulsion in anacceptable oil) or ion exchange resins, or as sparingly soluble salts.

In addition, other pharmaceutical delivery systems may be employed suchas liposomes and emulsions well known in the art. Certain organicsolvents such as dimethylsulfoxide also may be employed. Additionally,the β-hairpin peptidomimetics of the invention may be delivered using asustained-release system, such as semipermeable matrices of solidpolymers containing the therapeutic agent. Various sustained-releasematerials have been established and are well known by those skilled inthe art. Sustained-release capsules may, depending on their chemicalnature, release the compounds for a few weeks up to over 100 days.Depending on the chemical nature and the biological stability of thetherapeutic agent, additional strategies for protein stabilization maybe employed.

As the β-hairpin pepdidomimetics of the invention may contain chargedresidues, they may be included in any of the above-describedformulations as such or as pharmaceutically acceptable salts.Pharmaceutically acceptable salts tend to be more soluble in aqueous andother protic solvents than are the corresponding free base forms.

The β-hairpin peptidomimetics of the invention, or compositions thereof,will generally be used in an amount effective to achieve the intendedpurpose. It is to be understood that the amount used will depend on aparticular application.

For topical administration to treat or prevent infections atherapeutically effective dose can be determined using, for example, thein vitro assays provided in the examples. The treatment may be appliedwhile the infection is visible, or even when it is not visible. Anordinary skilled expert will be able to determine therapeuticallyeffective amounts to treat topical infections without undueexperimentation.

For systemic administration, a therapeutically effective dose can beestimated initially from in vitro assays. For example, a dose can beformulated in animal models to achieve a circulating p-hairpinpeptidomimetic concentration range that includes the IC₅₀ as determinedin the cell culture (i.e. the concentration of a test compound that islethal to 50% of a cell culture). Such information can be used to moreaccurately determine useful doses in humans.

Initial dosages can also be determined from in vivo data, e.g. animalmodels, using techniques that are well known in the art. One havingordinary skills in the art could readily optimize administration tohumans based on animal data.

Dosage amount for applications as anti-HIV agents may be adjustedindividually to provide plasma levels of the β-hairpin peptidomimeticsof the invention which are sufficient to maintain the therapeuticeffect. Therapeutically effective serum levels may be achieved byadministering multiple doses each day.

In cases of local administration or selective uptake, the effectivelocal concentration of the D-hairpin peptidomimetics of the inventionmay not be related to plasma concentration. One having the skills in theart will be able to optimize therapeutically effective local dosageswithout undue experimentation.

The amount of β-hairpin peptidomimetics administered will, of course, bedependent on the subject being treated, on the subject's weight, theseverity of the affliction, the manner of administration and thejudgement of the prescribing physician.

The anti-HIV therapy may be repeated intermittently while infections aredetectable or even when they are not detectable. The therapy may beprovided alone or in combination with other drugs, such as for exampleother anti-HIV agents or anti cancer agents, or anti inflammatory agentsor other antimicrobial agents.

Normally, a therapeutically effective dose of the β-hairpinpeptidomimetics described herein will provide therapeutic benefitwithout causing substantial toxicity.

Toxicity of the β-hairpin peptidomimetics of the invention herein can bedetermined by standard pharmaceutical procedures in cell cultures orexperimental animals, e.g., by determining the LD₅₀ (the dose lethal to50% of the population) or the LD₁₀₀ (the dose lethal to 100% of thepopulation). The dose ratio between toxic and therapeutic effect is thetherapeutic index. Compounds which exhibit high therapeutic indices arepreferred. The data obtained from these cell culture assays and animalstudies can be used in formulating a dosage range that is not toxic foruse in humans. The dosage of the β-hairpin peptidomimetics of theinvention lies preferably within a range of circulating concentrationsthat include the effective dose with little or no toxicity. The dosagemay vary within the range depending upon the dosage form employed andthe route of administration utilized. The exact formulation, route ofadministration and dose can be chosen by the individual physician inview of the patient's condition (see, e.g. Fingl et al. 1975, In: ThePharmacological Basis of Therapeutics, Ch. 1, P. 1).

The following Examples illustrate the invention in more detail but arenot intended to limit its scope in any way. The following abbreviationsare used in these Examples:

-   -   HBTU: 1-benzotriazol-1-yl-tetaamethylurounium        hexafluorophosphate (Knorr et al. Tetrahedron Lett. 1989, 30,        1927-1930);    -   HOBt: 1-hydroxybenzotriazole;    -   DIEA: duisopropylethylamidne;    -   DIC: diisopropylcarbodiimide;    -   HOAT: 7-aza-1-hydroxybenzotriazole;    -   HATU: O-(7-aza-benzotriazole-1-yl)-N,N,N′,N′-tetramethyluronoium        hexafluorophosphate (Carpino et al. Tetrahedron Lett. 1994, 35,        2279-2281).

EXAMPLES

1. Peptide Synthesis

Coupling of the First Protected Amino Acid Residue to the Resin

The Synthesis was Carried Out Using a ACT 90 Synthesizer (AdvancedChemtec)

A) Preparation of Preloaded Rink amide Resin

11 g 1% DVB-Aminomethyl-PS (loading 1.14 mmol/g) from Rapp Polymer GmbH,Germany (H1020, no. 100/0002) was allowed to swell in CH₂Cl₂ (100 ml)for 12 h, the solvent was filtered off and the resin was suspended inDMF (1100 ml) for 30 min. After filtering off DMF, a solution of 1.2 eqp-{(R,S)-α-[1-(9H-Fluoren-9-yl)-methoxyformamido]-2,4-dimethoxybenzyl}-phenoxyaceticacid (Fmoc Rink linker, Novabiochem, Switzerland), 1.2 eq HOBT and 1.2eq. DIC in 50 ml DMF was given to the resin and shaken at 25° C. for 12h. The solution was filtered of and the resin was washed with DMF (3×)and CH₂Cl₂ (3×). The resin was dried under vacuum for 12 hours.

The Fmoc-group was removed by treatment with a solution of 40%piperidine in Do (191 ml) for 45 min at 25° C., the resin was washed DMF(1×), and the treatment was repeated. The resin was washed with DMF (1×)and CH₂Cl₂ (1×) and dried under vacuum for 12 hours. Loading wastypically 0.7-0.85 mMol/g.

1.0 g of Rink amide resin (0.85 mMol/g, 0.85 mmol) was filled into adried flask. The resin was suspended in CH₂Cl₂ (50 ml) and allowed toswell at room temperature under constant stirring for 60 min, thesolvent was filtered off and the resin was suspended in DMF (50 ml) for5 hours. After filtering off the solvent, the resin was treated with 5eqof the first suitably protected amino acid residue (see below), 5 eqHOBT, and 5 eq DIC in DMF (40 ml), the mixture was shaken at 25° C. for12 hours. The resin then was washed in the following order with CH₂Cl₂(1×), DMF (1×), CH₂Cl₂ (1×) and dried under vacuum for 5 hours. Loadingwas typically 0.4-0.55 mMol/g.

The following preloaded resin was prepared: Fmoc-Arg(Pbf)-NH-Rink amideresin.

B) Preparation of Preloaded Chlorotrityl Resin

0.5 g of 2-chlorotritylchloride resin (Barlos et al. Tetrahedron Lett.1989, 30, 3943-3946) (0.83 mMol/g, 0.415 mmol) was filled into a driedflask The resin was suspended in CH₂Cl₂ (2.5 ml) and allowed to swell atroom temperature under constant stirring for 30 min. The resin wastreated with 0.415 mMol (1 eq) of the first suitably protected aminoacid residue (see below) and 284 μl (4 eq) of diisopropylethylarine(DIBA) in CH₂Cl₂ (2.5 ml), the mixture was shaken at 25° C. for 4 hours.The resin colour changed to purple and the solution remained yellowish.The resin was shaken (CH₂Cl₂/MeOH/DIEA: 17/2/1), 30 ml for 30 min; thenwashed in the following order with CH₂Cl₂ (1×), DMF (1×), CH₂Cl₂ (1×),MeOH (1×), CH₂Cl₂(1×), MeOH (1×), CH₂Cl₂ (2×), Et₂O (2×) and dried undervacuum for 6 hours.

Loading was typically 0.6-0.7 mMol/g.

The following preloaded resin was prepared:Fmoc-Arg(Pbf)O-chlorotritylresin.

Synthesis of the Fully Protected Peptide Fragment

The synthesis was carried out using a Syro-peptide synthesizer(Multisyntech) using 24 to 96 reaction vessels. In each vessel wasplaced 60 mg (weight of the resin before loading) of the above resin.The following reaction cycles were programmed and carried out:

Step Reagent Time 1 CH₂Cl₂, wash and swell (manual) 3 × 1 min. 2 DMF,wash and swell 1 × 5 min 3 20% piperidine/DMF 1 × 5 min. 4 DMF, wash 5 ×2 min. 5 5 equiv. Fmoc amino acid/DMF/NMP 2/1 1 × 120 min. +5 eq. HBTU+5 eq. HOBt +5 eq. DIEA 6 DMF, wash 4 × 2 min. 7 CH₂Cl₂, wash (at theend of the synthesis) 3 × 2 min.

Steps 3 to 6 are repeated to add each amino-acid.

Formation of Disulfide Bridge (Interstrand Linkage)

0.05 mmol of peptide-carrying resin was swelled in 3 mL of dry DCM for 1h and after filtering off the DCM, with dry DMF (3 mL) for overnight.Then 10 equivalents of iodine solution in DMF (6 mL) was added to thereactor and stirred for 1.5 h. The resin was filtered and the freshsolution of iodine (10 equivalents) in DMF (6 mL) was added and stirredfor another 3 h. The resin was filtered and washed thoroughly severaltimes with DMF and DCM.

Cleavage and Deprotection of the fully Protected Peptide Fragment

Cleavage from the resin and full deprotection of the peptide were doneby 7.5 mL of the cleavage mixture TFA:TIS:H₂O (95:2.5:2.5) for 3.5 h.The resin was filtered and the cleaved peptide was collected in a tubeand evaporated to dryness under vaccum. The crude peptide was dissolvedin 20% AcOH in water (7 mL) and extracted with isopropyl ether (4 mL)for three times. The aqueous layer was collected and evaporated todryness. For final oxidation of the cysteine (for formation of disulfidebridge), air was passed through the diluted solution of crude peptide inH₂O (6 nL) for 12 h.

Purification of the End-Product

The water phase was dried under vacuum and then the product purified bypreparative reverse phase HPLC.

The products were analysed by ESI-MS and after lyophilisation theproducts were obtained as a white powder. The analytical data comprisingHPLC retention times and ESI-MS are shown in table I and table 2.

Analytical HPLC retention times (RT, in minutes) were determined using aVYDAC 218MS5215 column with the following solvents A (H₂O+0.02% TFA) andB (CH3CN) and the gradient: 0 min: 92% A, 8% B; 8 min: 62% A 38% B; 9-12min: 0% A, 100% B.

Examples 1-3 (n=4, n′=6) are shown in table 1. The peptides weresynthesized starting with the amino acid Arg which was grafted to theresin. Starting resin was Fmoc-Arg(Pbf)-Rink-amide resin, which wasprepared as described above. The linear peptides were synthesized onsolid support according to procedure described above in the followingsequence: Resin-P4-P3-P2-P1-^(L)Pro-^(D)Lys-P1′-P2′-P3′-P4′-P5′-P6′;disulfide bridge formation, cleavage from the resin, deprotection andpurification were effected as indicated.

HPLC-retention times (minutes) were determined using the gradientdescribed above.

Examples 4 and 5 (n=4, n′=6) are shown in table 1. The peptides weresynthesized starting with the amino acid Arg which was grafted to theresin. Starting resin was Fmoc-Arg(Pbf)-Rink-amide resin, which wasprepared as described above. The linear peptides were synthesized onsolid support according to procedure described above in the followingsequence: Resin-P4-P3-P2-P1-^(L)Pro-^(D)Pro-P1′-P2′-P3′-P4′-P5′-P6′;disulfide bridge formation, cleavage from the resin, deprotection andpurification were effected as indicated.

HPLC-retention times (minutes) were determined using the gradientdescribed above.

Example 6 (n=4, n′=6) is shown in table 1. The peptide was synthesizedstarting with the amino acid Arg which was grafted to the resin.Starting resin was Fmoc-Arg(Pbf)-Rink-amide resin, which was prepared asdescribed above. The linear peptide was synthesized on solid supportaccording to procedure described above in the following sequence:Resin-P4-P3-P2-P1-^(L)Pro-^(L)Lys-P1′-P2′-P3′-P4-P5′-P6′; disulfidebridge formation, cleavage from the resin, deprotection and purificationwere effected as indicated.

HPLC-retention time (minutes) was determined using the gradientdescribed above.

Example 7 and 10-19 (n=5, n′=7) are shown in table 2. The peptides weresynthesized starting with the amino acid Arg which was grafted to theresin. Starting resin was Fmoc-Arg(Pbf)-Rink-amide resin, which wasprepared as described above. The linear peptides were synthesized onsolid support according to procedure described above in the followingsequence:Resin-P5-P4-P3-P2-P1-^(L)Pro-^(D)Pro-P1′-P2′-P3′-P4′-P5′-P6′-P7′;disulfide bridge formation, cleavage from the resin, deprotection andpurification were effected as indicated.

HPLC-retention times (minutes) were determined using the gradientdescribed above: Ex. 7 (4.27), Ex. 10 (4.13), Ex. 11 (3.68), Ex. 12(2.28), Ex. 13 (4.13), Ex. 14 (5.96), Ex. 15 (5.76), Ex. 16 (5.82), Ex.17 (5.90), Ex. 18 (5.90), Ex. 19 (5.84).

Example 8 (n=5, n′=7) is shown in table 2. The peptide was synthesizedstarting with the amino acid Arg which was grafted to the resin.Starting resin was Fmoc-Arg(Pbf)-Rink-amide resin, which was prepared asdescribed above. The linear peptide was synthesized on solid supportaccording to procedure described above in the following sequence:Resin-P5-P4-P3-P2-P1-^(L)Pro-^(D)Pro-P1′-P2′-P3′-P4′-P5′-P6′-P7′, andthe disulfide bridge was formed. The resin was then swelled in dry DCMfor 0.5 hrs. DCM was filtered off and 5 mL of dry DCM was added to theresin. 0.5 mL (2.92 mmol) of DIPEA and 0.125 mL (1.32 mmol) of aceticanhydride were added to the resin and stirred for 4 hrs. The resin wasfiltered and washed thoroughly with DCM, DMF, DCM, MeOH, Et₂O and driedin vaccum. The peptide was cleaved from the resin, deprotected andpurified as indicated.

HPLC-retention time was determined using the gradient described above:4.33 minutes.

Example 9 (n=5, n′=7) is shown in table 2. The peptide was synthesizedstarting with the amino acid Arg which was grafted to the resin.Starting resin was Fmoc-Arg(Pbf)-Rink-amide resin, which was prepared asdescribed above. The linear peptide was synthesized on solid supportaccording to procedure described above in the following sequence:Resin-P5-P4 P3-P2-P1-^(L)Pro-^(D)Pro-P1′-P2′-P3′-P4′-P5′-P6′-P7′ and thedisulfide bridge was formed. 2.5 mL of dry TIF and 200 μL of acetone wasadded to the reactor followed by addition of 2.5 mL of 50:50 (H₂O:Acetic acid) and stirred for 4 hrs. The solution of NaCNBH₃ (120 mg,1.90 mmol) in THF (2 mL) was added to the reactor and stirred for 4 hrs.Then the solvent was filtered and washed with DCM, DMF, DCM, MeOH, Et₂Oand dried in vaccum. The peptide was cleaved from the resin, deprotectedand purified as indicated.

HPLC-retention times was determined using the gradient described above:4.37 minutes.

Example 20 (n=5, n′=7) is shown in table 2. The peptide was synthesizedstarting with the amino acid Arg which was grafted to the resin.Starting resin was Fmoc-Arg(Pbf)-chlorotrityl resin, which was preparedas described above. The linear peptide was synthesized on solid supportaccording to procedure described above in the following sequence:Resin-P5-P4-P3-P2-P1-^(L)Pro-^(D)Pro-P1′-P2′-P3′-P4′-P5′-P6′-P7′;disulfide bridge formation, cleavage from the resin, deprotection andpurification were effected as indicated.

HPLC-retention time was determined using the gradient described above:4.35 minutes.

Example 21 (n=5, n′=7) is shown in table 2. The peptide was synthesizedstarting with the amino acid Arg which was grafted to the resin.Starting resin was Fmoc-Arg(Pbf)-Rink-amide resin, which was prepared asdescribed above. The linear peptide was synthesized on solid supportaccording to procedure described above in the following sequence:Resin-P5-P4-P3-P2-P1-[(b1)-154*]-P1′-P2′-P3′-P4′-P5′-P6′-P7′; disulfidebridge formation, cleavage from the resin, deprotection and purificationwere effected as indicated. *Template [(b1)-154] is(2S,6S,9S)-6-amino-2-carboxymethyl-3,8-diazabicyclo-[4,3,0]-nonane-1,4-dione

HPLC-retention time was determined using the gradient described above:4.02 minutes.

Example 22 (n=5, n′=7) is shown in table 2. The peptide was synthesizedstarting with the amino acid Arg which was grafted to the resin.Starting resin was Fmoc-Arg(Pbf)-Rink-amide resin, which was prepared asdescribed above. The linear peptide was synthesized on solid supportaccording to procedure described above in the following sequence:Resin-P5-P4-P3-P2-P1-AMPA-P1′-P2′-P3′-P4′-P5′-P6′-P7′; disulfide bridgeformation, cleavage from the resin, deprotection and purification wereeffected as indicated.

HPLC-retention time was determined using the gradient described above:4.62 minutes.

Example 23 (n=5, n′=7) is shown in table 2. The peptide was synthesizedstarting with the amino acid Arg which was grafted to the resin.Starting resin was Fmoc-Arg(Pbf)-Rink-amide resin, which was prepared asdescribed above. The linear peptide was synthesized on solid supportaccording to procedure described above in the following sequence:Resin-P5-P4-P3-P2-P1-^(D)Pro-^(L)Pro-P1′-P2′-P3′-P4′-P5′-P6′-P7′;disulfide bridge formation, cleavage from the resin, deprotection andpurification were effected as indicated.

HPLC-retention time was determined using the gradient described above:4.13, 4.40* minutes. * The MS is showing the correct mass.

Example 24 (n=5, n′=7) is shown in table 2. The peptide was synthesizedstarting with the amino acid Arg which was grafted to the resin.Starting resin was Fmoc-Arg(Pbf)-Rink-amide resin, which was prepared asdescribed above. The linear peptide was synthesized on solid supportaccording to procedure described above in the following sequence:Resin-P5-P4-P3-P2-P1-^(L)Pro-^(L)Pro-P1′-P2′-P3′-P4′-P5′-P6′-P7′;disulfide bridge formation, cleavage from the resin, deprotection andpurification were effected as indicated.

HPLC-retention time was determined using the gradient described above:4.08 minutes.

Example 25 (n=5, n′=7) is shown in table 2. The peptide was synthesizedstarting with the amino acid Arg which was grafted to the resin.Starting resin was Fmoc-Arg(Pbf)-Rink-amide resin, which was prepared asdescribed above. The linear peptide was synthesized on solid supportaccording to procedure described above in the following sequence:Resin-P5-P4-P3-P2-P-^(L)Pro-^(D)Pic-P1′-P2′-P3′-P4′-P5′-P6′-P7′;disulfide bridge formation, cleavage from the resin, deprotection andpurification were effected as indicated.

HPLC-retention time was determined using the gradient described above:4.47 minutes.

TABLE 1 Examples 1-6, n = 4, n′ = 6 Example Sequ.ID P6′ P5′ P4′ P3′ P2′P1′ Template P1 P2 P3 P4 RT Purity %^(a)) [M + H]/2 1 SEQ ID NO: 1 ArgArg 2-Nal Cys Tyr Lys ^(D)Lys^(L)Pro Tyr Cit Cys Arg-NH₂ 3.75 98 862.6 2SEQ ID NO: 2 Arg Arg 2-Nal Cys Tyr Lys ^(D)Lys^(L)Pro Tyr Cit CysArg-NH₂ 3.87 96 876.3 3 SEQ ID NO: 3 Arg Arg 2-Nal Cys Tyr Lys^(D)Lys^(L)Pro Arg Cit Cys Arg-NH₂ 3.28 97 858.4 4 SEQ ID NO: 4 Arg Arg2-Nal Cys Tyr Lys ^(D)Pro^(L)Pro Tyr Arg Cys Arg-NH₂ 4.62 100 845.9 5SEQ ID NO: 5 Arg Arg 2-Nal Cys Tyr Arg ^(D)Pro^(L)Pro Tyr Arg CysArg-NH₂ 4.83 98 860.0 6 SEQ ID NO: 6 Arg Arg 2-Nal Cys Tyr Arg^(L)Lys^(L)Pro Tyr Cit Cys Arg-NH₂ 4.10 96 875.9 ^(a))%-puritity ofcompounds after prep. HPLC. cysteines at position P3′ and P3 are linkedby a disulfide bridge

TABLE 2 Examples 7-25, n = 6, n′ = 7 Example Sequ.ID P7′ P6′ P5′ P4′ P3′P2′ P1′ 7 SEQ ID NO: 7 H-Arg Arg 2-Nal Cys Tyr Cit Lys 8 SEQ ID NO: 8AcArg^(b)) Arg 2-Nal Cys Tyr Cit Lys 9 SEQ ID NO: 9 iPrArg^(c)) Arg2-Nal Cys Tyr Cit Lys 10 SEQ ID NO: 10 H-^(D)Arg Arg 2-Nal Cys Tyr CitLys 11 SEQ ID NO: 11 H-Arg Arg Trp Cys Tyr Cit Lys 12 SEQ ID NO: 12H-Arg Arg F(pNH₂) Cys Tyr Cit Lys 13 SEQ ID NO: 13 H-Arg Arg W(6-Cl) CysTyr Cit Lys 14 SEQ ID NO: 14 H-(EA)G Arg 2-Nal Cys Tyr Cit Lys 15 SEQ IDNO: 15 H-(PrA)G Arg 2-Nal Cys Tyr Cit Lys 16 SEQ ID NO: 16 H-(BA)G Arg2-Nal Cys Tyr Cit Lys 17 SEQ ID NO: 17 H-(EGU)G Arg 2-Nal Cys Tyr CitLys 18 SEQ ID NO: 18 H-(PrGU)G Arg 2-Nal Cys Tyr Cit Lys 19 SEQ ID NO:19 H-(BGU)G Arg 2-Nal Cys Tyr Cit Lys 20 SEQ ID NO: 20 H-Arg Arg 2-NalCys Tyr Cit Lys 21 SEQ ID NO: 21 H-Arg Arg 2-Nal Cys Tyr Cit Lys 22 SEQID NO: 22 H-Arg Arg 2-Nal Cys Tyr Cit Lys 23 SEQ ID NO: 23 H-Arg Arg2-Nal Cys Tyr Cit Lys 24 SEQ ID NO: 24 H-Arg Arg 2-Nal Cys Tyr Cit Lys25 SEQ ID NO: 25 H-Arg Arg 2-Nal Cys Tyr Cit Lys Example Template P1 P2P3 P4 P5 Purity %^(a)) [M + H]/2 7 ^(D)Pro^(L)Pro Tyr Arg Cit CysArg-NH₂ 88 1003.6 8 ^(D)Pro^(L)Pro Tyr Arg Cit Cys Arg-NH₂ 100 1023.8 9^(D)Pro^(L)Pro Tyr Arg Cit Cys Arg-NH₂ 95 1025.1 10 ^(D)Pro^(L)Pro TyrArg Cit Cys Arg-NH₂ 98 1003.6 11 ^(D)Pro^(L)Pro Tyr Arg Cit Cys Arg-NH₂100 997.4 12 ^(D)Pro^(L)Pro Tyr Arg Cit Cys Arg-NH₂ 100 985.3 13^(D)Pro^(L)Pro Tyr Arg Cit Cys Arg-NH₂ 100 1015.3 14 ^(D)Pro^(L)Pro TyrArg Cit Cys Arg-NH₂ 84 1010.3 15 ^(D)Pro^(L)Pro Tyr Arg Cit Cys Arg-NH₂100 982.0 16 ^(D)Pro^(L)Pro Tyr Arg Cit Cys Arg-NH₂ 89 989 17^(D)Pro^(L)Pro Tyr Arg Cit Cys Arg-NH₂ 96 1003.0 18 ^(D)Pro^(L)Pro TyrArg Cit Cys Arg-NH₂ 99 1009.9 19 ^(D)Pro^(L)Pro Tyr Arg Cit Cys Arg-NH₂86 989.0 20 ^(D)Pro^(L)Pro Tyr Arg Cit Cys Arg-OH 100 1004.2 21 (b1)-154Tyr Arg Cit Cys Arg-NH₂ 97 1011.1 22 AMPA Tyr Arg Cit Cys Arg-NH₂ 100979.3 23 ^(L)Pro^(D)Pro Tyr Arg Cit Cys Arg-NH₂ 100 1002.9 24^(L)Pro^(L)Pro Tyr Arg Cit Cys Arg-NH₂ 100 1002.9 25 ^(D)Pic^(L)Pro TyrArg Cit Cys Arg-NH₂ 100 1010.1 ^(a))%-puritity of compounds after prep.HPLC. ^(b))Ac: Acetyl ^(c))iPr: Isopropyl cysteines at position P4′ andP4 are linked by a disulfide bridge (b1)-154 is(2S,6S,9S)-6-Amino-2-carboxymethyl-3,8-diazabicyclo-[4,3,0]-nonane-1,4-dione2. Biological Methods2.1. Preparation of the Peptides

Lyophilized peptides were weighed on a Microbalance (Mettler MT5) anddissolved in sterile water to a final concentration of 1 mM unlessstated otherwise. Stock solutions were kept at +4° C., light protected.

2.2. Ca²⁺⁻ assay: CXCR4Antagonizing Activity of the Peptides

3-4 Mio CXCR4 transfected pre-B cells [see references 1, 2 and 3, below]per measurement were resuspended in 200 μl MSB (20 mM4-(2-Hyddroxyethyl)-piperazin-1-ethansulfonic acid (HEPES), 136 mM NaCl,4.8 mM KCl and 1 mM CaCl₂) containing 5 mM D-Glucose and were loadedwith 0.75 μl of 1 mM Fura-2-acetoxymethylester for 17 minutes at 37° C.The cells were washed free from Fura-2-AM with a platelet centrifuge andresuspended in 800 R1 MSB containing 5 mM D-Glucose. The peptides to beadministered were diluted to a 100 fold end concentration in MSB/0.2%PPL, and 8 pl were injected. [Ca²⁺ ]_(i)-dependent fluorescence changein response to single or sequential stimulation with the peptide wasrecorded with a fluorimeter at an excitation wavelength of 340 nM and anend emission wavelength of 510 nM [see ref. 4, below]. Measurements weredone under continuous stirring at 37° C. The signal intension wascalibrated with 3 mM4 CaCl₂/1 nM lonomycin (maximalfura-2-acetoxymethylester saturation) and 10 μM MnCl₂ (minimalFura-2-acetoxymethylester saturation) and [Ca²⁺]_(i)-changes arepresented in % fura-2-acetoxymethylester saturation. The rate of[Ca²⁺]_(i)-changes was calculated on the basis of the initial[Ca²⁺]_(i)-changes and plotted in dependence of chemokine concentrationto obtain a sigmoidal curve and to determine the IC₅₀ values.

MSB: 20 nmM HEPES, 136 mM NaCl, 4.8 mM KCl, 1 mM CaCl₂.2H₂O, pH 7.4;Osmolarity: 310 mOsm adjusted with NaOH or HCl, adjusted with dH₂O orPBS.

MSB plus: 5 mM D-glucose in MSB (50 mg/50 mL).

Fura 2-acetoxymethylester: 1 mM stock solution in dimethylsulfoxide.

2.3. FIGS-Assay™

The assay was performed according to ref. 5, below. Stock dilutions ofthe peptides (10 mM) were prepared by dissolving in 10 mM Tris-HCl atroom temperature. Stock solutions were kept at +4° C., light protected.Working dilutions were prepared extemporaneously by serial dilution inPhosphate Buffered Saline (PBS) and added in a final volume of 10 μLdirectly to the cell cultures. After 48 hours of co-cultivation thecultures were rinsed with PBS and then exposed toglutaraldehyde/formaldehyde (0.2%/2%) in PBS for five minutes. Forphotometric quantification the fixed cultures were subsequentlyincubated with ortho-nitro-phenyl-galactopyranoside (ONPG) as aO-galactosidase substrate, which was enzymatically converted into thechromophore ortho-nitrophenol (ONP). The read out is directly obtainedby measuring optical density of wells at 405 nm in an IEMS 96 well-platereader.

2.4. Cytotoxicity Assay

The cytotoxicity of the peptides to HELA cells (Acc57) and COS-7 cells(CRL-1651) was determined using the MTl reduction assay [see ref. 6 and7, below]. Briefly the method was as follows: HELA cells and COS-7 cellswere seeded at 7.0·10³ and, respectively, 4.5·10³ cells per well andgrown in 96-well microtiter plates for 24 hours at 37° C. at 5% CO₂. Atthis point, time zero (Tz) was determined by MTT reduction (see below).The supernatant of the remaining wells was discarded and fresh mediumand the peptides in serial dilutions of 12.5, 25 and 50 μM were pipetedinto the wells. Each peptide concentration was assayed in triplicate.Incubation of the cells was continued for 48 hours at 37° C. at 5% CO₂.Wells were then washed once with PBS and subsequently 100 μl MTT reagent(0.5 mg/mL in medium RPMI1640 and, respectively, DMEM) was added to thewells. This was incubated at 37° C. for 2 hours and subsequently themedium was aspirated and 100 μl isopropanol was added to each well. Theabsorbance at 595 nm of the solubilized product was measured(OD₅₉₅peptide). For each concentration averages were calculated fromtriplicates. The percentage of growth was calculated as follows:(OD₅₉₅peptide-OD₅₉₅Tz-OD₅₉₅Empty well)/(OD₅₉₅Tz-OD₅₉₅Empty well)×100%and was plotted for each peptide concentration.

The LC 50 values (Lethal Concentration, defined as the concentrationthat kills 50% of the cells) were determined for each peptide by usingthe trend line function of EXCEL (Microsoft Office 2000) for theconcentrations (50, 25, 12.5 and 0 μM), the corresponding growthpercentages and the value −50, (=TREND(C50:C0,%50:%0,−50))

2.5. Cell Culture

‘CCR5’ cells were cultured in DMEM medium with 4500 mg/mL glucose, 10%fetal bovine serum (FBS), supplemented with 50 U/ml Penicillin and 50μg/ML Streptomycin (Pen/Strept.). Hut/4-3 cells were maintained in RPMImedium, 10% FBS, supplemented with Pen/Strept. and 10 mM HEPES. BELAcells and CCRF-CEM cells were maintained in RPMI1640 plus 5% FBS,Pen/Strept and 2 mM L-Glutamine. Cos-7 cells were grown in DMEM mediumwith 4500 mg/ml glucose supplemented with 10% FCS, Pen/Strept. and 2 MML-Glutamine. All cell lines were grown at 37° C. at 5% CO₂. Cell media,media supplements, PBS-buffer, HEPES, Pen/Strept., L-Glutamine and serawere purchased from Gibco (Pailsey, UK). All fine chemicals came fromMerck (D)armstadt, Germany).

2.6. Hemolysis

The peptides were tested for their hemolytic activity against human redblood cells (hRBC). Fresh hRBC were washed three times with phosphatebuffered saline (PBS) by centrifugation for 10 min at 2000×g. Peptidesat a concentration of 100 μM were incubated with 20% v/v hRBC for 1 hourat 37-C. The final erythrocyte concentration was approximately 0.9×10⁹cells per mL. A value of 0% resp. 100% cell lysis was determined byincubation of the hRBC in the presence of PBS alone and respectively0.1% Triton X-100 in H₂O. The samples were centrifuged and thesupernatant was 20-fold diluted in PBS buffer and the optical density(OD) of the sample at 540 nM was measured. The 100% lyses value(OD₅₄₀H₂O) gave an OD540 of approximately 1.3-1.8. Percent hemolysis wascalculated as follows: (OD₅₄₀peptide/OD₅₄₀H₂O)×100%.

2.7. Chemotactic Assay (Cell Migration Assay)

The chemotactic response of CCRF-CEM cells to a gradient of stromalcell-derived factor 1 a (SDF-1) was measured using disposable assayplates from Neuroprobe (5 μ pore size) (Gaithersburg, Md.), according tothe manufacturer's directions and references therein [especially ref. 8,below]. Briefly, one 175 cm² flask was washed once with Dubecco'sphosphate buffered saline (DPBS), and trypsinized for 10 minutes oruntil cells had lifted. The trypsin was neutralized by the addition offresh medium containing serum and the cells were pelleted, washed oncein DPBS, and resuspended at 1-0.5×10⁷ cells/ml in RPM!+0.5% bovine serumalbumin (BSA). 451 μl of cell suspension were mixed with 5μ of 10-foldconcentrated PEM peptide diluted in the same assay medium. 35 μl of thismixture were applied to the top of the assay filter. The cells wereallowed to migrate (at 37°) into the bottom chamber of the assay platecontaining 1 nM SDF-1. After 4 hours, the filter was removed and MTT wasadded to the migrated cells to a final concentration of 0.5 mg/ml, andincubated for a further 4 hours. After labeling with MTT, all medium wasremoved and 100 μl of isopropanol+10 mM HCl were added to the cells. Theoptical absorbance at 595 nm (ABS₅₉₅) was read using a Tecan Geniosplate reader with Magellan software. The number of cells migrated wasdetermined by comparing ABS₅₉₅ values against a standard curve generatedwith a known number of cells in the assay plate and were plotted againstSDF-1 concentration to obtain a sigmoidal curve and to determine theIC₅₀ values. The values for IC50 were determined using the Trendlinefunction in Microsoft Excel by fitting a logarithmic curve to theaveraged datapoints.

2.7 Results

The results of the experiments described above are indicated in Table 3hereinbelow.

IC₅₀ (μM) FIGS ™ Cell IC₅₀ (nM) % inhibition St.dev. CytotoxicityHemolysis migration Ex. Ca²⁺ assay at 200 nM at 200 nM LC₅₀ at 100 μMassay 1 2404.1 12.9 7.8 75 0.4 n.d. 2 1000 3.8 14.5 58 0.9 n.d. 3 490.35.7 3.9 52 0.7 n.d. 4 848.3 26.0 5.6 >300 0.3 n.d. 5 131.5 16.4 3.5 670.7 n.d. 7 n.d. n.d. n.d. 56 0.3 0.55 8 13.9 90.6 3.4 226 0.1 5.0 1021.5 82.0 9.4 118 0.6 0.55 12 13.9 71.3 7.0 226 0.1 5.0 15 n.d. n.d.n.d. n.d. n.d. 0.57 16 n.d. n.d. n.d. n.d. n.d. 1.04 18 n.d. n.d. n.d.n.d. n.d. 0.65 19 n.d. n.d. n.d. n.d. n.d. 0.85 20 15.5 At 300 nM: 100n.d. 138 0.2 n.d. 21 316.2 29.6 10.8 82 0.8 n.d. 22 80.3 22.5 1.6 75 0.1n.d. 24 100 17.1 8.9 67 1.1 n.d n.d.: not determined

REFERENCES

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1. A compound of the general formula

is selected from the group consisting of ^(D)Pro-^(L)Pro and^(L)Pro-^(D)Pro; Z and Z¹ are chains of n and, respectively, n′ α-aminoacid residues whereby either n is 4 and n′ is 6 or n is 5 and n′ is 7,the positions of said amino acid residues in said chain Z being countedfrom the N-terminal amino acid and the positions of said amino acidresidues in chain Z¹ being counted from the C-terminal amino acid,whereby these amino acid residues are if n is 4 and n′ is 6 the aminoacid residues in positions 1 to 4 of the chain Z and in positions 1′ to6′ in chain Z¹ are: P1: Tyr or Arg; P2: L-citrulline (Cit) or Arg; P3:Cys; P4: Arg-NH₂; P1′: Lys or Arg; P2′: Tyr; P3′: Cys; P4′:L-2-naphthylalanine (2-Nal); P5′: Arg; and P6′: Arg; Cys at P3 and P3′can form a disulfide bridge; and if n is 5 and n′ is 7, the amino acidresidues in positions 1 to 5 in chain Z and in positions 1′ to 7′ inchain Z¹ are: P1: Tyr; P2: Arg; P3: Cit; P4: Cys; P5: Arg or Arg-NH₂P1′: Lys; P2′: Cit; P3′: Tyr; P4′: Cys; P5′: 2-Nal, Trp,L-para-aminophenylalanine (F(pNH₂)) or L-6-C1-Tryptophan (W(6-C1)); P6′:Arg; P7′: ^(D)Arg, Arg, Ac-Arg, iPr-Arg, N-(2-aminoethyl)glycine((EA)G), N-(3-aminopropyl)glycine ((PrA)G), N-(4-amino-n-butyl)glycine((BA)G), N-(2-guanidinoethyl)glycine ((EGU)G),N-(3-guanidino-n-propyl)glycine ((PrGU)G), orN-(4-guanidino-n-butyl)glycine ((BGU)G); Cys at P4 and P4′ can form adisulfide bridge or an enantiomer thereof or pharmaceutically acceptablesalts thereof.
 2. The compound according to claim 1, wherein the α-aminoacid residues in positions 1 to 4 of the chain Z and the α-amino acidresidues in positions 1′ to 6′ chain Z¹ are: P1: Tyr, or Arg; P2: Cit,or Arg; P3: Cys; P4: Arg-NH₂; P1′: Lys, orArg; P2′: Tyr; P3′: Cys; P4′:2-Nal; P5′: Arg; P6′: Arg; and Cys at P3 and P3′ can form a disulfidebridge.
 3. The compound according to claim 1, wherein the α-amino acidresidues in positions 1 to 5 of the chain Z and the α-amino acidresidues in positions 1′ to 7′ chain Z¹ are: P1: Tyr; P2: Arg; P3: Cit;P4: Cys; P5: Arg, or Arg-NH₂; P1′: Lys; P2′: Cit; P3′: Tyr; P4′: Cys;P5′: 2-Nal, Trp, F(pNH₂), or W(6-C1); P6′: Arg; P7′: ^(D)Arg, Arg,Ac-Arg, iPr-Arg, (EA)G, (PrA)G, (BA)G, (EGU)G, (PrGU)G, or (BGU)G; andCys at P4 and P4′ can form a disulfide bridge.
 4. The compound offormula I according to claim 1, wherein

is ^(D)Pro-^(L)Pro, n is 5, n′ is 7 and the amino acid residues inpositions 1 to 5 of the chain Z and the amino acid residues in positions1′ to 7′ chain Z¹ are: P1: Tyr; P2: Arg; P3: Cit; P4: Cys; P5: Arg-NH₂;P1′: Lys; P2′: Cit; P3′: Tyr; P4′: Cys; P5′: 2-Nal; P6′: Arg; and P7′:Arg; and Cys at P4′ and P4 forming a disulfide bridge.
 5. The compoundof formula I according to claim 1, wherein

is ^(D)Pro-^(L)Pro, n is 5, n′ is 7 and the amino acid residues inpositions 1 to 5 of the chain Z and the amino acid residues in positions1′ to 7′ chain Z¹ are: P1: Tyr; P2: Arg; P3: Cit; P4: Cys; P5: Arg-NH₂;P1′: Lys; P2′: Cit; P3′: Tyr; P4′: Cys; P5′: 2-Nal; P6′: Arg; and P7′:Ac-Arg; and Cys at P4′ and P4 forming a disulfide bridge.
 6. Thecompound of formula I according to claim 1, wherein

is ^(D)Pro-^(L)Pro, n is 5, n′ is 7 and the amino acid residues inpositions 1 to 5 of the chain Z and the amino acid residues in positions1′ to 7′ chain Z¹ are: P1: Tyr; P2: Arg; P3: Cit; P4: Cys; P5: Arg-NH₂;P1′: Lys; P2′: Cit; P3′: Tyr; P4′: Cys; P5′: 2-Nal P6′: Arg; and P7′:^(D)Arg; and Cys at P4′ and P4 forming a disulfide bridge.
 7. Thecompound of formula I according to claim 1, wherein

is ^(D)Pro-^(L)Pro, n is 5, n′ is 7 and the amino acid residues inpositions 1 to 5 of the chain Z and the amino acid residues in positions1′ to 7′ chain Z¹ are: P1: Tyr; P2: Arg; P3: Cit; P4: Cys; P5: Arg-NH₂;P1′: Lys; P2′: Cit; P3′: Tyr; P4′: Cys; P5′: Phe(pNH₂); P6′: Arg; andP7′: Arg; and Cys at P4′ and P4 forming a disulfide bridge.
 8. Thecompound of formula I according to claim 1, wherein

is ^(D)Pro-^(L)Pro, n is 5, n′ is 7 and the amino acid residues inpositions 1 to 5 of the chain Z and the amino acid residues in positions1′ to 7′ chain Z¹ are: P1: Tyr; P2: Arg; P3: Cit; P4: Cys; P5: Arg-NH₂;P1′: Lys; P2′: Cit; P3′: Tyr; P4′: Cys; P5′: 2-Nal; P6′: Arg; and P7′:(PrA)G; and Cys at P4′ and P4 forming a disulfide bridge.
 9. Thecompound of formula I according to claim 1, wherein

is ^(D)Pro-^(L)Pro, n is 5, n′ is 7 and the amino acid residues inpositions 1 to 5 of the chain Z and the amino acid residues in positions1′ to 7′ chain Z¹ are: P1: Tyr; P2: Arg; P3: Cit; P4: Cys; P5: Arg; P1′:Lys; P2′: Cit; P3′: Tyr; P4′: Cys; P5′: 2-Nal; P6′: Arg; and P7′: Arg;and Cys at P4′ and P4 forming a disulfide bridge.
 10. A pharmaceuticalcomposition containing a compound according to claim 1 and apharmaceutically inert carrier.
 11. The composition according to claim10 in a form suitable for a mode of administration selected from thegroup consisting of oral, topical, transdermal, injection, buccal,transmucosal, pulmonary and inhalation.
 12. The composition according toclaim 10 in a form selected from the group consisting of tablets,dragees, capsules, solutions, liquids, gels, plaster, creams, ointments,syrup, slurries, suspensions, spray, nebuliser or suppositories.
 13. Thecomposition according to claim 11 in a form selected from the groupconsisting of tablets, dragees, capsules, solutions, liquids, gels,plaster, creams, ointments, syrup, slurries, suspensions, spray,nebuliser or suppositories.
 14. A method for treating a disordermediated by or resulting from CXCR4 activity which comprises:administering to a subject in need of such treatment an effective amountof a compound according to claim
 1. 15. A process for the manufacture ofcompounds according to claim 1, which process comprises (a) coupling anappropriately functionalized solid support with an appropriatelyN-protected derivative of that amino acid which in the desiredend-product is in position 4 of Z if n is 4 or in position 5 of Z if nis 5, any functional group which may be present in said N-protectedamino acid derivative being likewise appropriately protected; (b)removing the N-protecting group from the product thus obtained; (c)coupling the product thus obtained with an appropriately N-protectedderivative of that amino acid which in Z of the desired end-product isone position nearer the N-terminal amino acid residue, any functionalgroup which may be present in said N-protected amino acid derivativebeing likewise appropriately protected; (d) removing the N-protectinggroup from the product thus obtained; (e) repeating steps (c) and (d)until the N-terminal amino acid residue of Z has been introduced; (f)coupling the product thus obtained with a compound of the generalformula

 is as defined in claim 1 and X is an N-protecting group; or,alternatively, (fa) coupling the product obtained in step (e) with anappropriately N-protected derivative of ^(L)Pro or ^(D)Pro; (fb)removing the N-protecting group from the product thus obtained; and (fc)coupling the product thus obtained with an appropriately N-protectedderivative of ^(D)Pro and, respectively, ^(L)Pro; (g) removing theN-protecting group from the product obtained in step (f) or (fc); (h)coupling the product thus obtained with an appropriately N-protectedderivative of that amino acid which in the desired end-product is inposition 1 of Z¹, any functional group which may be present in saidN-protected amino acid derivative being likewise appropriatelyprotected; (i) removing the N-protecting group from the product thusobtained; (j) coupling the product thus obtained with an appropriatelyN-protected derivative of that amino acid which in the desiredend-product is one position farther away from position 1 of Z′, anyfunctional group which may be present in said N-protected amino acidderivative being likewise appropriately protected; (k) removing theN-protecting group from the product thus obtained; (l) repeating steps(j) and (k) until all amino acid residues of Z¹ have been introduced;(m) if desired, selectively deprotecting one or several protectedfunctional group(s) present in the molecule and appropriatelysubstituting the reactive group(s) thus liberated; (n) if desired,forming one or two interstrand linkage(s) between side-chains ofappropriate amino acid residues at opposite positions of the β-strandregion; (o) detaching the product thus obtained from the solid supportand removing any protecting groups present on functional groups of anymembers of the chain of amino acid residues and, if desired, anyprotecting group(s) which may in addition be present in the molecule;and (p) if desired, converting the product thus obtained into apharmaceutically acceptable salt or converting a pharmaceuticallyacceptable, or unacceptable, salt thus obtained into the correspondingfree compound of formula I or into a different, pharmaceuticallyacceptable, salt.
 16. A process for the manufacture of compoundsaccording to claim 1, which process comprises: (a) coupling anappropriately functionalized solid support with an appropriatelyN-protected derivative of that amino acid which in the desiredend-product is in position 4 of Z if n is 4 or in position 5 of Z if nis 5, any functional group which may be present in said N-protectedamino acid derivative being likewise appropriately protected; (b)removing the N-protecting group from the product thus obtained; (c)coupling the product thus obtained with an appropriately N-protectedderivative of that amino acid which in Z of the desired end-product isone position nearer the N-terminal amino acid residue, any functionalgroup which may be present in said N-protected amino acid derivativebeing likewise appropriately protected; (d) removing the N-protectinggroup from the product thus obtained; (e) repeating steps (c) and (d)until the N-terminal amino acid residue of Z has been introduced; (f)coupling the product thus obtained with a compound of the generalformula

 is selected from the group consisting of ^(D)Pro-^(L)Pro and^(L)Pro-^(D)Pro and X is an N-protecting group; or, alternatively, (fa)coupling the product obtained in step (e) with an appropriatelyN-protected derivative of ^(L)Pro or ^(D)Pro; (fb) removing theN-protecting group from the product thus obtained; and (fc) coupling theproduct thus obtained with an appropriately N-protected derivative of^(D)Pro and, respectively, ^(L)Pro; (g) removing the N-protecting groupfrom the product obtained in step (f) or (fc); (h) coupling the productthus obtained with an appropriately N-protected derivative of that aminoacid which in the desired end-product is in position 1 of Z¹, anyfunctional group which may be present in said N-protected amino acidderivative being likewise appropriately protected; (i) removing theN-protecting group from the product thus obtained; (j) coupling theproduct thus obtained with an appropriately N-protected derivative ofthat amino acid which in the desired end-product is one position fartheraway from position 1 of Z¹, any functional group which may be present insaid N-protected amino acid derivative being likewise appropriatelyprotected; (k) removing the N-protecting group from the product thusobtained; (l) repeating steps (j) and (k) until all amino acid residuesof Z¹ have been introduced; (m) if desired, selectively deprotecting oneor several protected functional group(s) present in the molecule andappropriately substituting the reactive group(s) thus liberated; (n) ifdesired, forming one or two interstrand linkage(s) between side-chainsof appropriate amino acid residues at opposite positions of the β-strandregion; (o) detaching the product thus obtained from the solid supportand removing any protecting groups present on functional groups of anymembers of the chain of amino acid residues and, if desired, anyprotecting group(s) which may in addition be present in the molecule;and (p) if desired, converting the product thus obtained into apharmaceutically acceptable salt or converting a pharmaceuticallyacceptable, or unacceptable, salt thus obtained into the correspondingfree compound of formula I or into a different, pharmaceuticallyacceptable, salt; but wherein a residue of N-(2-aminoethyl)glycine,N-(3-aminopropyl)glvcine, N-(4-amino-n-butyl)glycine,N-(2-guanidinoethyl)glycine, N-(3-guanidino-n-propyl)glycine orN-(4-guanidino-n-butyl)glycine is introduced by coupling with a leavinggroup-containing agent, followed by nucleophilic displacement withammonia and, respectively, guanidine.
 17. The process according to claim16, wherein the leaving group in said leaving group-containing acylatingagent is bromo, chloro or iodo acetic acid.